Nirogacestat, sold under the brand name Ogsiveo, is an

anti-cancer medication Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a cu ...

used for the treatment of

desmoid tumors Aggressive fibromatosis or desmoid tumor is a rare condition. Desmoid tumors are a type of fibromatosis and related to sarcoma, though without the ability to spread throughout the body (metastasize). The tumors arise from cells called fibrobla ...

. It is a selective

gamma secretase Gamma secretase is a multi-subunit protease complex, an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most ...

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

that is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. Nirogacestat was approved for medical use in the United States in November 2023. It is the first medication approved by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) for the treatment of desmoid tumors. The FDA considers it to be a

first-in-class medication A first-in-class medication is a prototype drug that uses a "new and unique mechanism of action" to treat a particular medical condition. While the Food and Drug Administration's Center for Drug Evaluation and Research tracks first-in-class medic ...

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

(EMA) considers it an

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

. and issued a positive opinion on its approval

Medical uses

Nirogacestat is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for adults with progressing desmoid tumors who require systemic treatment.

Adverse effects

Nirogacestat treatment has been associated with several notable adverse effects across multiple studies. Hypophosphatemia is a significant and common side effect, with an incidence exceeding 40% in patients with various cancers including desmoid tumors, sarcoma, metastatic breast cancer, and solid organ cancers. Gastrointestinal toxicity is another concern, and glucocorticosteroid pretreatment and post-treatment regimens have shown efficacy in mitigating these effects in clinical trials. Reproductive toxicity has been observed in animal studies, with findings including ovarian atrophy, amenorrhea, premature menopause, reduced testes weight, and decreased sperm concentration and motility; some of these effects may be irreversible. There is a possible risk of

non-melanoma skin cancer Skin cancers are cancers that arise from the skin. They are due to the development of abnormal cells that have the ability to invade or spread to other parts of the body. It occurs when skin cells grow uncontrollably, forming malignant tumo ...

development. ''In vivo'' rat studies showed embryotoxicity, including decreased body weight, implantation loss and

subcutis The subcutaneous tissue (), also called the hypodermis, hypoderm (), subcutis, or superficial fascia, is the lowermost layer of the integumentary system in vertebrates. The types of cells found in the layer are fibroblasts, adipose cells, and ma ...

edema at doses lower than the recommended human dose. Additionally, there has been a reported case of eruptive

milia A milium (: milia), also called a milk spot or an oil seed, is a clog of the eccrine sweat gland. It is a keratin-filled cyst that may appear just under the epidermis or on the roof of the mouth.Freedberg, et al. (2003). ''Fitzpatrick's Dermatolo ...

in association with nirogacestat therapy. Nirogacestat have been found to induce grade 1 or 2 adverse effects, with exception of hypophosphatemia at grade 3: * diarrhea * nausea and vomiting * abdominal pain * fatigue * maculopapular rash, folliculitis, hidradenitis * anorexia * fatigue * stomatitis * cough * alopecia * upper respiratory tract infection * dyspnea * headache * lymphopenia * trombocytopenia * liver toxicity (alanine transaminase and aspartate transaminase increase) * hypophosphatemia, hypokalemia * anaphylaxis * glycosuria * proteinuria

Pharmacology

Pharmacodynamics

Nirogacestat works as a gamma secretase inhibitor, which blocks the activation of the

Notch receptor __NOTOC__ __FORCETOC__ Notch proteins are a Protein family, family of type 1 transmembrane proteins that form a core component of the Notch signaling pathway, which is highly conserved in Animal, animals. The Notch extracellular domain mediates i ...

, stopping tumor growth. Nirogacestat's indirect action on Notch intracellular domain (NICD) and

amyloid precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of s ...

(APP) due to gamma-secretase inhibition are described in the table below. Nirogacestat's binding to gamma-secretase assessed with

cryogenic electron microscopy Cryogenic electron microscopy (cryo-EM) is a transmission electron microscopy technique applied to samples cooled to cryogenic temperatures. For biological specimens, the structure is preserved by embedding in an environment of vitreous ice. An ...

showed that it localises in the persenilin 1 catalytic subunit. Four

hydrogen bonds In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, covalently bonded to a mo ...

are involved in this interaction, where two come from lysine (position 380 within the amino-acid sequence of gamma-secretase) and two from leucine (position 432). Its aligment selectively obstructs the site of Notch cleavage by gamma-secretase, which occurs in its β-sheet, allowing inhibition of downstream Notch signalling. Nirogacestat trifluoropropyl derivative

Moreover, nirogacestat's pharmacophore is consistent with other gamma-secretase inhibitors (e.g., crenigacestat) in terms of three dimensional arrangement in the binding cavity. Leucine342 hydrogen bond interaction is shared amongst these compounds A slight modification of nirogacestat's structure, where the propyl group is substituted by a trifluoropropyl group, results in enhanced binding-pocket occupation and better inhibition.

Pharmacokinetics

Nirogacestat's pharmacokinetic parameters in patients with desmoid tumors are as follows:

Drug interactions

Nirogacestat can interfere with several drugs that are metabolised through cytochrome P450 pathways, especially through CYP3A family and CYP2C19. Additionally, gastric acid-neutralising medications impired its absorption and thus reduced its plasma concentration.

Chemistry

Physicochemical properties

Nirogacestat's chemical properties were evaluated ''in silico'' and ''in vitro'' in mice and are as follows:

Synthesis

Nirogacestat can be synthesised through the following pathway: Nirogacestat synthesis

2-(2,4-difluorophenyl)acetyl chloride (1) undergoes cyclisation reaction with ethene to yield 2. Then, 2 reacts with ''tert''-butyl (2''S'')-2-aminopentanoate, yielding 3 that is further hydrolysed to remove the ''tert''-butyl group, yielding 4. To finally obtain nirogacestat, 4 is reacted with 5 ( - -(2,2-dimethylpropylamino)-1,1-dimethyl-ethyl">-[2-(2,2-dimethylpropylamino)-1,1-dimethyl-ethylmidazol-4-ylzinate). Alternatively, 6 reacts with 7, where the trifluoromethylsulfonate moiety acts as a leaving group and the ''tert''-butyl moiety acts as a protecting group, to avoid the reaction of carboxyl group with amine group in 6. This reaction is performed in ''iso''-propanol and an inorganic acid (such as hydrobromic or hydrochloric acid). Obtained 8 undergoes cyclisation reaction using 9 (Carbonyldiimidazole">1,1'-carbonyldiimidazole) in a polar aprotic solvent, yielding 10. Then, reaction with 11 creates nirogacestat. Nirogacestat synthesis 2

The trifluoromethylsulfonyl group in 7 can be replaced with tert-butyloxycarbonyl group (Boc). Reaction of 10 with 11 is conducted a condensing agent, precisely ''O''-(1,2-dihydro-2-oxo-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) in ''N,N''-diisopropylethylamine. Formation of several side products should be addressed. The above synthetic pathway allows to minimise side product creation to less than 1%. An important example is adverse cyclisation of the product of reaction of 10 with 11 shown below (compound 12). To avoid this situation, to the mixture of 10 and 11, compound 6 and hydrobromic acid is added. Nirogacestat synthesis side product

Compounds 5 and 11 can be synthesised as follows: Nirogacestat intermediates synthesis

A undergoes reduction using diisobutylaluminium hydride (DIBAL-H) in dichloromethane (DCM), obtaining B. Then B is condensed with 2,2-dimethylpropan-1-amine with Sodium triacetoxyborohydride, Na(OAc)₃BH in DCM on a molecular sieve, yielding 5. To synthesise 11, 5 undergoes reduction with hydrogen on Palladium on carbon, Pd/C in methanol. Compound 6 and ''tert''-butyl (2''S'')-2-aminopentanoate may be synthesised using an enzyme-driven process, using respectively: ATA ω-

transaminase Transaminases or aminotransferases are enzymes that catalyze a transamination reaction between an amino acid and an α-keto acid. They are important in the synthesis of amino acids, which form proteins. Function and mechanism An amino acid con ...

with

isopropylamine Isopropylamine (also known as monoisopropyl amine, MIPA, or 2-propylamine) is an organic compound, an amine. It is a hygroscopic colorless liquid with ammonia-like odor. It is miscible with water and flammable. It is a valuable intermediate in c ...

pyridoxal phosphate Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependen ...

, phosphoric acid and potassium hydroxide;

alcohol dehydrogenase Alcohol dehydrogenases (ADH) () are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to N ...

, glucose dehydrogenase, glucose monohydrate, NAD⁺ in phosphate buffer and

glycerol Glycerol () is a simple triol compound. It is a colorless, odorless, sweet-tasting, viscous liquid. The glycerol backbone is found in lipids known as glycerides. It is also widely used as a sweetener in the food industry and as a humectant in pha ...

. This enzymatic process is used to obtain 6 from 2 while minimising stereoisomer side products (the reaction is selective towards the ''S'' isomer).

Crystalline forms

Nirogacestat can exist in several crystalline forms, where the form used clinically is an anhydrous dihydrobromide salt that has a primitive monoclinic Bravais lattice (form A). It exhibits high polymorphic purity of at least 80%. In water, it crystallises as small needles and does not change its lattice, suggesting stability. Other forms can change into form A in

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical compound and the simplest aliphatic Alcohol (chemistry), alcohol, with the chemical formula (a methyl group linked to a hydroxyl group, often ab ...

, suggesting instability. However, form A in methanol mixed with other reagents (

acetone Acetone (2-propanone or dimethyl ketone) is an organic compound with the chemical formula, formula . It is the simplest and smallest ketone (). It is a colorless, highly Volatile organic compound, volatile, and flammable liquid with a charact ...

trichloromethane Chloroform, or trichloromethane (often abbreviated as TCM), is an organochloride with the chemical formula, formula and a common solvent. It is a Volatility (chemistry), volatile, colorless, sweet-smelling, dense liquid produced on a large scale ...

, methyl-''tert''-butyl ether and ''N''-Methyl-2-pyrrolidone) changes its lattice. In clinical settings, this transformation is not observed.

History

Pre-clinical compound leading to discovery of nirogacestat

Preclinical studies assessed different functional group configurations of a compound with a common backbone. Initially, ''N''-

pyrrolidine Pyrrolidine, also known as tetrahydropyrrole, is an organic compound with the molecular formula (CH2)4NH. It is a cyclic secondary amine, also classified as a saturated heterocycle. It is a colourless liquid that is miscible with water and most ...

was selected for ''in vivo'' assay, which demonstrated significant inhibitory activity at gamma-secretase. Further studies aimed to optimise EC₅₀-plasma concentration coefficient, which led to selection of nirogacestat for further studies. The effectiveness of nirogacestat was evaluated in DeFi (NCT03785964), an international, multicenter, randomized (1:1), double-blind, placebo-controlled trial in 142 adult participants with progressing desmoid tumors not amenable to surgery. Participants were randomized to receive 150 milligrams (mg) of nirogacestat or placebo orally, twice daily, until disease progression or unacceptable toxicity. The main efficacy outcome measure was progression-free survival (the length of time after the start of treatment for which a person is alive and their cancer does not grow or spread). Objective response rate (a measure of tumor shrinkage) was an additional efficacy outcome measure. The pivotal clinical trial demonstrated that nirogacestat provided clinically meaningful and statistically significant improvement in progression-free survival compared to placebo. Additionally, the objective response rate was also statistically different between the two arms with a response rate of 41% in the nirogacestat arm and 8% in the placebo arm. The progression-free survival results were also supported by an assessment of patient-reported pain favoring the nirogacestat arm. As of 2021, nirogacestat was in

phase II clinical trials The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

for unresectable desmoid tumors. In addition, a

phase III clinical trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phase ...

, DeFi, was in progress for nirogacestat for adults with desmoid tumors and aggressive fibromatosis. The FDA granted the application for nirogacestat

priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...

fast track Fast Track, Fast track, or Fasttrack may refer to: Processes and systems * Fast track (FDA), a U.S. Food and Drug Administration expedited review program * Fast track (trade), the authority of the U.S. President to broker trade agreements with lim ...

breakthrough therapy Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "b ...

, and

designations. The FDA granted the approval of Ogsiveo to SpringWorks Therapeutics Inc.

Society and culture

Legal status

Nirogacestat was granted breakthrough therapy designation by the FDA in September 2019, for adults with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis. In June 2025, the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as the Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regar ...

of the

adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ogsiveo, intended for the treatment of adults with progressing desmoid tumors. The applicant for this medicinal product is SpringWorks Therapeutics Ireland Limited. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

Research

Neurological disorders

Since gamma-secretase inhibitors are involved in producing amyloid β-peptide from amyloid precursor protein (APP), they may have application in the treatment of

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. Nirogacestat tested in guiena pig brain showed amyloid β-lowering activity with ED₅₀ for amyloid β in guiena pig brain at 1.83 mg/kg, sc. Another study showed, that IC₅₀ values for cell-free enzyme assay (amyloid β_1-40), whole-cell assay (amyloid β_1-x) and

CD25 The interleukin-2 receptor alpha chain (also called Tac antigen, P55, and mainly CD25) is a protein involved in the assembly of the high-affinity interleukin-2 receptor, consisting of alpha (''IL2RA''), beta ('' IL2RB'') and the common gamma cha ...

+ B- and T- cells in fetal thymic organ culture are respectively 6.2 nM, 1.2 nm and 1.3 nM. However, human phase 2 clinical tria of nirogacestatl showed no benefit in altering APP processing by nirogacestat. Nirogacestat may be useful for treating several other neurological diseases, including hereditary cerebral hemorrhage with amyloidosis,

cerebral amyloid angiopathy Cerebral amyloid angiopathy (CAA) is a form of angiopathy in which amyloid beta peptide deposits in the walls of small to medium blood vessels of the central nervous system and meninges. The term ''congophilic'' is sometimes used because the pres ...

inclusion body myositis Inclusion body myositis (IBM) () (sometimes called sporadic inclusion body myositis, sIBM) is the most common inflammatory muscle disease in older adults. The disease is characterized by slowly progressive weakness and wasting of both proximal m ...

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

, mild cognitive impairment and Down's syndrome.

Hematological malignancies

Multiple myeloma

Five clinical trials evaluated efficacy of nirogacestat with other anticancer therapies in

multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibody, antibodies. Often, no symptoms are noticed initially. As it progresses, bone ...

: * UNIVERSAL – nirogacestat and allogeneic

CAR-T In biology, chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors—are receptor proteins that have been engineered to give T cells the new ability to target a specific ...

therapy ALLO-715. * MajesTEC-2 – nirogacestat an teclistamab * DREAMM 5 – nirogacestat in combination with belantamab mafodotin and

pomalidomide Pomalidomide, sold under the brand names Pomalyst and Imnovid, is an anti-cancer medication used for the treatment of multiple myeloma and AIDS-related Kaposi sarcoma. Pomalidomide was approved for medical use in the United States in February ...

Results showed moderate response rate and allowed reduction of belantamab dose. One important advese effect associated with this treatment regimen were ocular evenets, including keratopathy, decreased corrected visual acuity. DREAMM-5 clinical trial confirmed these findings. * MagnetisMM-4 – nirogacestat and elranatamab * PBCAR269A – nirogacestat and allogenic anit-'' BCMA'' CAR-T cell therapy,

fludarabine Fludarabine is a purine analogue and antineoplastic agent. It is generally used as its 5-O-phosphorylated form known as fludarabine phosphate, sold under the brand name Fludara among others. It is a chemotherapy medication used in the treatm ...

and

cyclophosphamide Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...

(terminated due to insufficient therapeutic effect.) Additionally, an ''in vitro'' and ''in vivo'' (plasma cells in healthy patients) study showed that nirogacestat rapidly increases membrane-bound BCMA receptor and decreases soluble BCMA concentrations, which in turn supports its potential to treat multiple myeloma. However, this effect was only temporary, suggesting that a steady sate is required to maintain its efficacy. Moreover, release of soluble BCMA into tear fluid is associated with keratopathy.

Lymphoblastic leukemia and T-cell lymphoblastic lymphoma

A clinical trial testing nirogacestat's usefulness in treating lymphoblastic malignancies was conducted and its results showed that it inhibited ''

HES4 Hes Family BHLH Transcription Factor 4 (HES4) is a protein encoded by a gene of the same name located on chromosome 1 in humans. It does not currently have a known mouse ortholog. HES4 plays a major role in key developmental processes, particula ...

'' gene expression in peripheral blood of treated patients. Since this transcription factor is involbed in Notch1-mediated T-cell development, this finding justifies further clinical trials to test its efficacy in blood cancers. ''In vitro'' studies in Notch1-mutated acute lymphoblastic leukemia cell lines confirmed ''HES4''-inhibition and also presented evidence for decereasing expression of ''

cMyc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' (MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes refer ...

'' regulator. Moreover, nirogacestat induced apoptosis markers, that is the active form of

caspase-3 Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the ''CASP3'' gene. ''CASP3'' orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also ...

and cleaved (inactivated) PARP expression in human acute lymphoblastic leukemia cells. One study tested a novel formulation of nirogacestat and

dexamethasone Dexamethasone is a fluorinated glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive pulmonary disease (COPD), croup, brain swelling, eye pain following eye su ...

, which were developed to be bound to a modified

lecithin Lecithin ( ; from the Ancient Greek "yolk") is a generic term to designate any group of yellow-brownish fatty substances occurring in animal and plant tissues which are amphiphilic – they attract both water and fatty substances (and so ar ...

nanoparticles, targeting lymphoma cells. ''In vitro'', this allowed to enhance dexamethasone-mediated cell death, through simultaneous

glucocorticoid receptor The glucocorticoid receptor (GR or GCR) also known by its gene name ''NR3C1'' ( nuclear receptor subfamily 3, group C, member 1) is the steroid receptor for glucocorticoids such as cortisol. The GR is expressed in almost every cell in the bod ...

hyperexpression and ''

BCL2 Bcl-2, encoded in humans by the ''BCL2'' gene, is the founding member of the apoptosis regulator proteins, Bcl-2 family, Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can eithe ...

'' inhibition. It also allowed to increase bone marrow accumulation. The peptide was synthesised from phopsphatidyletholamine bound to stearic acid chains and a pegyl group, an octapeptide (''N''-His-Arg-Pro-Tyr-Ile-Ala-His-Cys-''C'') and soy lecithin.

Chronic lymphoblastic leukemia

HG3 cell line represents a testing environment for drugs that affect the progression of chronic lymphoblastic leukemia. Nirogacestat is capable of decrease the viability of these cells (using ATP quantification assay) compared to

DMSO Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula . This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is ...

in both ''

NOTCH1 Neurogenic locus notch homolog protein 1 (Notch 1) is a protein encoded in humans by the ''NOTCH1'' gene. Notch 1 is a single-pass transmembrane receptor. Function This gene encodes a member of the Notch family. Members of this type 1 transm ...

'' wild-type and mutated cells (using

CRISPR/Cas9 Cas9 (CRISPR associated protein 9, formerly called Cas5, Csn1, or Csx12) is a 160 kilodalton protein which plays a vital role in the immunological defense of certain bacteria against DNA viruses and plasmids, and is heavily utilized in genetic ...

technology), suggesting a probable treatment regimen for this disease. When combined with a USP28 (ubiquitin specific peptidase 28) allosteric inhibition, this regimen was enhanced compared to nirogacestat alone. Both of these findings were statistically significant. Moreover, nirogacestat showed dose-dependent S and G₂-M

mitotic Mitosis () is a part of the cell cycle in eukaryotic cells in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis is an equational division which gives rise to genetically identical cells in which the t ...

phase inhibition in Notch1-mutated CLL cells, lowering cell viability.

Diffuse large B-cell lymphoma

Mutations in ''NOTCH2'' genes in diffuse large-B cell lymphoma (DLBCL) can cause a relatively common resistance to R-CHOP treatment regimen. Nirogacestat promotes ubiquitin-dependent Notch2 degradation via E3 ligases ( KLHL6 and

FBXW7 F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the ''FBXW7'' gene. Function This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The ...

), stopping mRNA expression of ''MYC'' and ''

KRAS ''KRAS'' ( Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the ce ...

'' genes, which are involved in downstream signalling leading to cell proliferation. Moreover, combination with an AKT inhibitor ipatasertib further enhanced apoptotic promotion in malignant R-CHOP-resistant lymphocytes B. However, the inhibitory constant (IC₅₀) of nirogacestat in dual ''KLHL6'' and ''FBXW7'' human DLBCL-xenotransplanted mutant mice (with a deletion in

degron A degron is a portion of a protein that is important in regulation of protein degradation rates. Known degrons include short amino acid sequences, structural motifs and exposed amino acids (often lysine or arginine) located anywhere in the protei ...

sites in E3 ligases, that recognise Notch2) was over two-times higher, than in the wild type.

Acute myeloid leukemia

Nirogacestat's chemoresistance reversion in combination in glasdegib was tested in three ''in vitro'' models, each representing a different subtype of acute myeloid leukemia (HL60 – AML M2 with ''

TP53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...

'' deletion and ''

CDKN2A ''CDKN2A'', also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 f ...

''^C238T, Kasumi-1 – AML M2 with AML1-

ETO ETO may refer to: Science and technology * Emitter turn off thyristor, a semiconductor device * Ethylene oxide, an organic compound * RUNX1T1, a gene * Efforts to Outcomes, software produced by Social Solutions Sports * ETO-SZESE Győr FKC, a Hung ...

fusion gene and OCI-AML3 – AML M4 with ''

NPM1 Nucleophosmin (NPM), also known as nucleolar phosphoprotein B23 or numatrin, is a protein that in humans is encoded by the ''NPM1'' gene. Gene In humans, the ''NPM1'' gene is located on the long arm of chromosome 5 (5q35). The gene spans 23 kb ...

'' and ''

DNMT3A DNA (cytosine-5)-methyltransferase 3A (DNMT3A) is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the ''DNMT3A'' gene. This enzyme is ...

''^R882c mutations) as well as a small pool of patient samples. The results were mixed, where in HL60 cells this combination both reversed quiescence and decreased viability with addition of

cytarabine Cytarabine, also known as cytosine arabinoside (ara-C), is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma. It is given b ...

than cytarabine alone. In OCI-AML3 and patient samples, only quiescence reversion was observed, whereas in Kasumi-1 – no differences were found.

Reverse transcriptase PCR Reverse transcription polymerase chain reaction (RT-PCR) is a laboratory technique combining reverse transcription of RNA into DNA (in this context called complementary DNA or cDNA) and amplification of specific DNA targets using polymerase chain ...

assay found that nirogacestat in combination with

significantly influenced expression of Notch-related genes (increased: '' DTX1 –'' an ubiquitin ligase, decreasing T-cell development in thymus, peripherial blood and spleen, ''

BCL2L11 Bcl-2-like protein 11, commonly called BIM (Bcl-2 Interacting Mediator of cell death), is a protein that in humans is encoded by the ''BCL2L11'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredit ...

'' – a protein involved in Bcl-2-related apoptosis ;decreased: ''

HES1 Transcription factor HES1 (hairy and enhancer of split-1) is a protein that is encoded by the ''Hes1'' gene, and is the mammalian homolog of the hairy gene in ''Drosophila.'' HES1 is one of the seven members of the Hes gene family (HES1-7). Hes g ...

'' – a transcription factor repressing '' NR3C1'' glucocorticoid receptor upregulation). This finding shows that nirogacestat poses an ability to reverse glucocorticoid resistance in AML, thereby significantly decreasing tumor mass. Moreover, glucocorticoid administration attenuated nirogacestat-induced gastrointestinal toxicity, by stopping

goblet cell Goblet cells are simple columnar epithelial cells that secrete gel-forming mucins, like mucin 2 in the lower gastrointestinal tract, and mucin 5AC in the respiratory tract. The goblet cells mainly use the merocrine method of secretion, secre ...

metaplasia Metaplasia () is the transformation of a cell type to another cell type. The change from one type of cell to another may be part of a normal maturation process, or caused by some sort of abnormal stimulus. In simplistic terms, it is as if the ...

related to Notch1 suppression, and increasing '' Math1'' gene. Nirogacestat also decreases

β-actin Actin beta (HUGO Gene Nomenclature Committee abbreviation ''ACTB''/ACTB) is one of six different actin isoforms which have been identified in humans. This is one of the two nonmuscle cytoskeletal actins. Actins are highly conserved proteins that ...

expression, disrupting cytosceletal structures. Additionally, nirogacestat treatment exhibits synergistics effects with

rapamycin Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ rejection, organ transplant rejection, treat a rare lung disease called lymphang ...

's antileukemic properties.

Splenic marginal zone lymphoma

''In vitro'' studies showed that concomitant nirogacestat administration with

decitabine Decitabine (i.e., 5-aza-2′-deoxycytidine), sold under the brand name Dacogen among others, acts as a nucleic acid synthesis inhibitor. It is a medication for the treatment of myelodysplastic syndromes, a class of conditions where certain blood ...

ibrutinib Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor ...

idelalisib Idelalisib, sold under the brand name Zydelig, is a medication used to treat certain blood cancers. Idelalisib acts as a phosphoinositide 3-kinase inhibitor; more specifically, it blocks P110δ, the delta isoform of the enzyme phosphoinositid ...

, and an investigational drug 3-dezaneplanocin A intensively increased cell deth in splenic marginal zone malignant lymphocytes.

Solid tumors

Colorectal cancer

In mouse with

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...

harboring mutated

adenomatous polyposis coli Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the ''APC'' gene. The APC protein is a Down-regulation, negative regulator that controls beta-catenin concentrations and i ...

gene (''APC''), that exhibit enhanced Notch signalling, nirogacestat decreased cell migration, invasion and growth.

Pancreatic adenocarcinoma

One study tested nirogacestat alone and with

gemcitabine Gemcitabine, sold under the brand name Gemzar, among others, is a chemotherapy medication used to treat cancers. It is used to treat testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder ca ...

pancreatic ductal adenocarcinoma The pancreas (plural pancreases, or pancreata) is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine ...

patient-derived xenografts in mice and showed that both treatment arms showed regression of cell division and decreased angiogenesis. Phase 2 clinical trial of nirogacestat in metastatic pancreatic cancer was terminated due to changes in Pfizer's strategy in drug development.

Venous thromboembolism Venous thrombosis is the blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off ( embolizes) and flows to the lun ...

is a serious complication of panceratic cancer that is mediated by

interleukin-6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...

(IL-6),

thyroid peroxidase Thyroid peroxidase, also called thyroperoxidase (TPO), thyroid specific peroxidase or iodide peroxidase, is an enzyme expressed mainly in the thyroid where it is secreted into colloid. Thyroid peroxidase oxidizes iodide ions to form iodine atoms ...

(TPO) and

tissue factor Tissue factor, also called platelet tissue factor or Coagulation factor III, is a protein present in subendothelial tissue and leukocytes which plays a major role in coagulation and, in humans, is encoded by ''F3'' gene. Its role in the blood c ...

(TF) secretion from tumor-associated

stromal cells Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucos ...

. Nirogacestat, in an ''in vivo'' study with mice injected with pancreatic adenocarcinoma cells, showed a steep decrease in these markers. This hyperexpression is also present in human plasma in patients with this malignancy. This effect was shown to be mediated by

Jagged ''Jagged'' is the fifteenth solo studio album by English musician Gary Numan, his first original album in over five years, following '' Pure'' in 2000. Stylistically ''Jagged'' was a development of its predecessor's chorus-driven, anthemic i ...

-Notch interaction.

Lung adenocarcinoma

Nirogacestat was shown to reverse resistance to tyrosine kinase inhibitors such as

gefitinib Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in targe ...

in EGFR-mutated

lung adenocarcinoma Adenocarcinoma of the lung is the most common type of lung cancer, and like other forms of lung cancer, it is characterized by distinct cellular and molecular features. It is classified as one of several non-small cell lung cancers (NSCLC), to d ...

, precisely the form where there exists a EGFR^T790M/L858R mutation.

Breast cancer

Nirogacestat emerged as a possible adjunctive treatment to taxane treatment of

triple-negative breast cancer Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification (i.e ...

. Notch receptor intracytoplasmic domain being internalised into a singnal-receiving cell, induces a signal transduction pathway associated with

pregnane X receptor In the field of molecular biology, the pregnane X receptor (PXR), also known as the steroid and xenobiotic sensing nuclear receptor (SXR) or nuclear receptor subfamily 1, group I, member 2 (NR1I2) is a protein that in humans is encoded by the ' ...

that causes

BCRP ATP-binding cassette super-family G member 2 is a protein that in humans is encoded by the ''ABCG2'' gene. ABCG2 has also been designated as CDw338 (cluster of differentiation w338). ABCG2 is a translocation protein used to actively pump drugs ...

, P-glycoprotein and CYP3A4 activation, causing drug resistance. It has a slight preference towards persenilin 2 versus 1 catalytic subunits of gamma-secretase. Nirogacestat's chemoresistance reversion in combination in glasdegib was tested in three ''in vitro'' models, each representing a different subtype of acute myeloid leukemia (HL60 – AML M2 with ''

'' deletion and ''

''^C238T, Kasumi-1 – AML M2 with AML1-

fusion gene and OCI-AML3 – AML M4 with ''

'' and ''

''^R882c mutations) as well as a small pool of patient samples. The results were mixed, where in HL60 cells this combination both reversed quiescence and decreased viability with addition of

than cytarabine alone. In OCI-AML3 and patient samples, only quiescence reversion was observed, whereas in Kasumi-1 – no differences were found.

assay found that nirogacestat in combination with

significantly influenced expression of Notch-related genes (increased: '' DTX1 –'' an ubiquitin ligase, decreasing T-cell development in thymus, peripherial blood and spleen, ''

'' – a protein involved in Bcl-2-related apoptosis ;decreased: ''

related to Notch1 suppression, and increasing '' Math1'' gene. Nirogacestat also decreases

expression, disrupting cytosceletal structures. Additionally, nirogacestat treatment exhibits synergistics effects with

's antileukemic properties. In human mitoxantrone-resistant breast carcinoma cell line nirogacestat inhibits their migration, but shows no antiproliferative effects. In

estrogen receptor Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...

-positive

metastatic breast cancer Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary l ...

, a phase 1 study showed that co-administration of nirogacestat with

exemestane Exemestane, sold under the brand name Aromasin among others, is a medication used to treat breast cancer. It is a member of the class of antiestrogens known as aromatase inhibitors. Some breast cancers require estrogen to grow. Those cancers ha ...

inhibited metastasis. Since

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

associated with tumor development is regulater by

YAP Yap (, sometimes written as , or ) traditionally refers to an island group located in the Caroline Islands of the western Pacific Ocean, a part of Yap State. The name "Yap" in recent years has come to also refer to the state within the Federate ...

TAZ Taz or TAZ may refer to: Geography *Taz (river), a river in western Siberia, Russia *Taz Estuary, the estuary of the river Taz in Russia People * Taz people, an ethnic group in Russia ** Taz language, a form of Northeastern Mandarin spoken by ...

cytoplasm translocation from nucleus, nirogacestat was tested as a possible inhibitor of cytoplasm transport of these transcription factors. In one study, it was shown that nirogacestat significantly reduced cytoplasmatic concentration of YAP and TAZ, suggesting antiangiogenic activity in breast cancer tumor environment. Nirogacestat and ovarian granulosa cell proliferation

Nirogacestat and ovarian granulosa cell proliferation

Ovarian granulosa cell tumor

Similarly to abovementioned diseases, the mechanism of action of nirogacestat supported the launch of a phase 2 clinical trial. Proposed influence of nirogacestat on these tumors is that overactivation of Notch causes ''

FOXL2 Forkhead box protein L2 is a protein that in humans is encoded by the ''FOXL2'' gene. Function FOXL2 (OMIM 605597) is a transcription factor belonging to the forkhead box (FOX) superfamily, characterized by the forkhead box/winged-helix DNA-b ...

'' hyperexpression, which is inhibited by this drug. It was confirmed by studying nirogacestat's effect on a cell line, in which a mutation in ''FOXL2''^C134W is present that causes enhanced gamma-secretase activity on SMAD-mediated signalling pathway. However, nirogacestat's usefulness in this model is controvesial, since some studies show no clinical benefit.

Prostate cancer

''In vitro'' studies of nirogacestat in

castration-resistant prostate cancer Prostate cancer is the uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through screening tests, typically blood tests that che ...

cells showed, that it reversed

enzalutamide Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castrati ...

and

docetaxel Docetaxel (DTX or DXL), sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small-cel ...

resistance and itself halted the further development of cancerous malignancy. In PTEN-deficient cancer cells, nirogacestat induced tumor growth arrest by inducing

cellular senescence Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of appro ...

Hepatocellular carcinoma and squamous cell carcinoma

Nirogacestat has the ability of suppresing

hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. HCC most common ...

growth and metastasis, by decreasing

Stat3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respon ...

and Akt signalling activity beside Notch1 inhibition. Concomitant administration of

sorafenib Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer (hepatocellular carcinoma), FLT3-ITD positive AML and ra ...

further decreased hepatocellular carcinoma spheroids (stem-like cells), where this effect is attributed to nirogacestat's ability to reduce Notch1-induced sorafenib resistance via decrasing epithelial-mesenchymal transition (EMT), where it is associated with attenuated expression of EMT-related genes (i.e., Snail1,

N-cadherin Cadherin-2 also known as Neural cadherin (N-cadherin), is a protein that in humans is encoded by the ''CDH2'' gene. CDH2 has also been designated as CD325 (cluster of differentiation 325). Cadherin-2 is a transmembrane protein expressed in multi ...

ABCG2 ATP-binding cassette super-family G member 2 is a protein that in humans is encoded by the ''ABCG2'' gene. ABCG2 has also been designated as CDw338 (cluster of differentiation w338). ABCG2 is a translocation protein used to actively pump drugs ...

, Nanog and

Oct4 Oct-4 (octamer-binding transcription factor 4), also known as POU5F1 ( POU domain, class 5, transcription factor 1), is a protein that in humans is encoded by the ''POU5F1'' gene. Oct-4 is a homeodomain transcription factor of the POU family ...

), enhanced expression of

E-cadherin Cadherin-1 or Epithelial cadherin (E-cadherin), is a protein that in humans is encoded by the ''CDH1'' gene (not to be confused with the APC/C activator protein CDH1). Mutations are correlated with Hereditary diffuse gastric cancer, gastric, Here ...

and inhibition of survival signalling pathways ( Mek/Erk and PI3K/Akt). It also reduced tumor angiogenesis ''in vivo''. Similar mechanisms are responsible for nirogacestat/erlotinib combination's ability to reduce

head and neck This article describes the anatomy of the head and neck of the human body, including the brain, bones, muscles, blood vessels, nerves, glands, nose, mouth, teeth, tongue, and throat. Structure Bones The head rests on the top part of the vertebr ...

and oral squamous cell carcinoma cell invasion and tumor growth.

Melanoma

Notch signalling pathway increases MAPK pathway in uveal and

cutaneous melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...

. Therefore, it can cause resistance to

cobimetinib Cobimetinib, sold under the brand name Cotellic, is an anti-cancer medication used to treat melanoma and histiocytic neoplasms. Cobimetinib is a MEK inhibitor. Cobimetinib is marketed by Genentech. The most common side effects include diarrhea ...

. In BRAF^V600E metastatic melanoma, nirogacestat was shown to inhibit resistance to therapy, whereas in GNAQ^Q209L uveal melanoma it diminished cancer cell migration. Overall, it was also shown to inhibit

c-jun Transcription factor Jun is a protein that in humans is encoded by the ''JUN'' gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only l ...

and Erk1/2 activation.

Cholangiocarcinoma

TAZ zinc finger containing transcription factors are involved in development of

cholangiocarcinoma Cholangiocarcinoma, also known as bile duct cancer, is a type of cancer that forms in the bile ducts. Symptoms of cholangiocarcinoma may include abdominal pain, yellowish skin, weight loss, generalized itching, and fever. Light colored stoo ...

. Since its expression is increased indirectly by Notch pathway, nirogacestat may be a potential treatment for this disease. The mechanism explaining this potential application is that Notch induces METLL3 expression, that causes ''N''-6-methyladenosine modification of TAZ mRNA, which causes its hyperexpression.

Other diseases

Osteolytic diseases

''In vivo'' studies showed nirogacestat's activity at receptor activator of nuclear factor-κB ligand (RANKL), which is implicated in osteoclastogenesis and

lipopolysaccharide Lipopolysaccharide (LPS), now more commonly known as endotoxin, is a collective term for components of the outermost membrane of the cell envelope of gram-negative bacteria, such as '' E. coli'' and ''Salmonella'' with a common structural archit ...

-induced

bone resorption Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood. The osteoclasts are multi-nuclea ...

. It inhibited bone resorption and attenuated mRNA expression of osteoclast-specific markers (

calcitonin receptor The calcitonin receptor (CT) is a G protein-coupled receptor that binds the peptide hormone calcitonin and is involved in maintenance of calcium homeostasis, particularly with respect to bone formation and metabolism. CT works by activating the ...

, tartarate-resistant acid phosphatase,

cathepsin K Cathepsin K, abbreviated CTSK, is an enzyme that in humans is encoded by the ''CTSK'' gene. Function The protein encoded by this gene is a cysteine cathepsin, a lysosomal cysteine protease involved in bone remodeling and resorption. This pr ...

, dendritic cell-specific transmembrane protein, V-ATPase d2, nuclear factor of activated T-cells cytoplasmic 1).

Recessive dystrophic epidermolysis bullosa

Notch signalling pathway is involved in profibrotic activity, causing dystrophic epiderolysis bullosa. Nirogacestat can be a potential treatment for this disease, since it reduces fibroblast contractility and secretion of TGF-β1 and

collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...

Polycystic kidney disease

In one study, nirogacestat was an agent tested among other compounds, including another Notch inhibitor –

dibenzazepine Dibenzazepine (iminostilbene) is a chemical compound with two benzene functional group, rings fused to an azepine ring (chemistry), ring. Many pharmaceuticals, such as carbamazepine, oxcarbazepine, and depramine, are based on a dibenzazepine struc ...

. Both of them were shown to inhibit

forskolin Forskolin (coleonol) is a labdane diterpene produced by the plant '' Coleus barbatus'' (blue spur flower). Other names include pashanabhedi, Indian coleus, makandi, HL-362, mao hou qiao rui hua. As with other members of the large diterpene class o ...

-mediated

Notch3 Neurogenic locus notch homolog protein 3 (Notch 3) is a protein that in humans is encoded by the ''NOTCH3'' gene. Function This gene encodes the third discovered human homologue of the ''Drosophila melanogaster'' type I membrane protein notc ...

expression in ADPKD (Autosomal Dominant Polycystic Kidney Disease) cells.

Microvillus inclusion disease

Studies in mice pretreated with

tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome ...

in order to create

myosin Myosins () are a Protein family, family of motor proteins (though most often protein complexes) best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are adenosine triphosphate, ATP- ...

Vb-deficient and -mutated

intestinal epithelium The intestinal epithelium is the single cell layer that forms the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelium its main functions are absorptio ...

cells showed that nirogacestat halted mislocalisation of enterocyte sodium transporters (e.g.,

sodium–hydrogen antiporter 3 Sodium–hydrogen antiporter 3 also known as sodium–hydrogen exchanger 3 (NHE3) or solute carrier family 9 member 3 (SLC9A3) is a protein that in humans is encoded by the ''SLC9A3'' gene. SLC9A3 is a sodium–hydrogen antiporter. It is found ...

and sodium/glucose cotransporter 1) only in deficient, but not mutated, mice tissues. Even though this study was not aimed at utilising nirogacestat as a potential treatment, it showed that total loss and malfunction of myosin Vb contribute to different subtypes of microvillus inclusion disease.

Retinal degenerative diseases

Transplantation of retinal organoids derived from human

embryonic stem cells Embryonic stem cells (ESCs) are Cell potency#Pluripotency, pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre-Implantation (human embryo), implantation embryo. Human embryos reach the blastocyst stage 4� ...

and

induced pluripotent stem cells Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from a somatic cell. The iPSC technology was pioneered by Shinya Yamanaka and Kazutoshi Takahashi in Kyoto, J ...

in conjunction with nirogacestat administration in mice presenting with retinal degeneration increased both rod and cone generation in the retina. However, this process is highly inefficient, since most of the transplanted cells undergo apoptosis, outflow from the injection site, graft rejection and produce inflammatory response.

Diabetes

Concomitant administration of nirogacestat and a ''

FOXO1 Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the ''FOXO1'' gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glyco ...

'' inhibitor in

streptozocin Streptozotocin or streptozocin (INN, USP) (STZ) is a naturally occurring alkylating antineoplastic agent that is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. It is used in medicine for treating certain canc ...

-induced diabetic mice was shown to increase enteroendocrine progenitor cells differentiation into β-cells, which secrete

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

, thereby decreasing plasma glucose concentration. This effect influenced hepatic glucose homeostasis, by increasing the expression of

glucokinase Glucokinase () is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase is expressed in cells of the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important ro ...

(consequently inducing

glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body. Glycogen functions as one of three regularly used forms ...

synthesis) , and suppressing gluconeogenic enzymes

glucose-6-phosphatase The enzyme glucose 6-phosphatase (EC 3.1.3.9, G6Pase; systematic name D-glucose-6-phosphate phosphohydrolase) catalyzes the hydrolysis of glucose 6-phosphate, resulting in the creation of a phosphate group and free glucose: : D-glucose 6-pho ...

and

phosphoenolpyruvate carboxykinase Phosphoenolpyruvate carboxykinase (, PEPCK) is an enzyme in the lyase family used in the metabolic pathway of gluconeogenesis. It converts oxaloacetate into phosphoenolpyruvate and carbon dioxide. It is found in two forms, cytosolic and mitoc ...

expression.

Analogs

The 2,4-difluorophenyl moiety of nirogacestat exhibits strongly polarised carbon-fluorine bonds; therefore it can create hydrogen bonds with biological targets. This characteristic led to development of novel molecules that can be utilised in treatment of several cancers. Their structure is based on 1-(2,4-difluorophenyl)-5-oxopyrrolidine-3-carboxylic acid, which is conjugated with other moieties. Smallest EC₅₀ values were shown for following compounds.

References

{{Authority control Amides Chemotherapy Fluoroarenes Gamma secretase inhibitors Imidazoles Orphan drugs Secondary amines Tetralins Neopentyl compounds