Silmitasertib (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

), codenamed CX-4945, is a

small-molecule Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ar ...

inhibitor of protein kinase CK2 (

casein kinase II Casein ( , from Latin ''caseus'' "cheese") is a family of related phosphoproteins ( αS1, aS2, β, κ) that are commonly found in mammalian milk, comprising about 80% of the proteins in cow's milk and between 20% and 60% of the proteins in hum ...

), a constitutively active

serine/threonine-specific protein kinase A serine/threonine protein kinase () is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human prot ...

that is overexpressed in several types of

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

s. Silmitasertib is in clinical trials for use as an

adjunct Adjunct may refer to: * Adjunct (grammar), words used as modifiers * Adjunct professor, a rank of university professor * Adjuncts, sources of sugar used in brewing * Adjunct therapy used to complement another main therapeutic agent, either to impr ...

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...

in the treatment 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 ...

(bile duct cancer), is in phase I and II clinical trials for the treatment of recurrent

Sonic Hedgehog Sonic hedgehog protein (SHH) is encoded for by the ''SHH'' gene. The protein is named after the character ''Sonic the Hedgehog (character), Sonic the Hedgehog''. This signaling molecule is key in regulating embryonic morphogenesis in all animals ...

(SHH)

medulloblastoma Medulloblastoma is a common type of primary brain cancer in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the cerebellum, or posterior fossa. The brain is divided into two ...

, and in

preclinical development In drug development, preclinical development, also termed preclinical studies or nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug ...

for other cancers, including hematological and lymphoid malignancies. In January 2017, it was granted

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment o ...

status by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

for advanced cholangiocarcinoma. It is being developed by Senhwa Biosciences of Taiwan.

Mechanism of action

Silmitasertib interacts

competitively Competition is a rivalry where two or more parties strive for a common goal which cannot be shared: where one's gain is the other's loss (an example of which is a zero-sum game). Competition can arise between entities such as organisms, indivi ...

with the

ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...

-binding site of CK2 subunit alpha. This leads to inhibition of several downstream

signaling pathways Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...

, including PI3K/Akt.

COVID-19 infections

In SARS-CoV-2 (COVID-19) infected

Caco-2 Caco-2 (from ''Cancer coli'', "colon cancer") is an immortalized cell line of human colorectal adenocarcinoma cells. It is primarily used as a model of the intestinal epithelial barrier. In culture, Caco-2 cells spontaneously differentiate into a ...

cells, the phosphorylase activity of

casein kinase 2 Casein kinase 2 ()(CK2/CSNK2) is a serine/threonine-selective protein kinase that has been implicated in cell cycle control, DNA repair, regulation of the circadian rhythm, and other cellular processes. De-regulation of CK2 has been linked to tumor ...

(CK2) is increased resulting in phosphorylation of several cytoskeletal proteins. These infected cells also display CK2-containing

filopodia Filopodia (singular filopodium) are slender cytoplasmic projections that extend beyond the leading edge of lamellipodia in migrating cells. Within the lamellipodium, actin ribs are known as ''microspikes'', and when they extend beyond the lam ...

protrusions associated with budding viral particles. Hence the protrusions may assist the virus in infecting adjacent cells. In these same cells, the CK2 inhibitor silmitasertib displayed potent antiviral activity. Senhwa Biosciences and the US

National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government The federal government of the United States (U.S. federal government or U ...

have announced that they will evaluate the efficacy of silmitasertib in treating COVID-19 infections.

History

CX-4945 was originated by now-defunct Cylene Pharmaceuticals of San Diego, California, as the culmination of a lengthy process of rational, structure-based

molecular modification Molecular modification is chemical alteration of a known and previously characterized lead compound for the purpose of enhancing its usefulness as a drug. This could mean enhancing its specificity for a particular body target site, increasing its ...

of a

lead compound A lead compound (, i.e. a "leading" compound, not to be confused with various compounds of the metallic element lead) in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, but ...

known to have

PARP inhibitor PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP). They are developed for multiple indications, including the treatment of heritable cancers. Several forms of cancer are more dependent on ...

activity. Among a large series of compounds built around a benzo 'c'' ,6 aphthyridine-8-carboxylic acid scaffold, CX-4945 was chosen for its high potency and selectivity as an inhibitor of CK2. Preclinical

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

studies conducted in mice, rats, and dogs confirmed that CX-4945 had satisfactory

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. ...

when given by mouth and did not block

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compo ...

, while experiments in mice confirmed its inhibition of solid-tumor growth in a dose-dependent manner. Clinical trials in humans began in 2010, making CK-4945 the first CK2 inhibitor to reach this stage of drug development. The International Nonproprietary Name silmitasertib was proposed in 2010 and recommended by the

World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...

in 2011.

References

Naphthyridines Orphan drugs Protein kinase inhibitors Carboxylic acids Chloroarenes {{antineoplastic-drug-stub