ABT-737 is a

small molecule In 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 are small molecules; ...

drug that inhibits

Bcl-2 Bcl-2, encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can either inhibit or induce it. It was the first a ...

and

Bcl-xL B-cell lymphoma-extra large (Bcl-xL), encoded by the BCL2-like 1 gene, is a transmembrane molecule in the mitochondria. It is a member of the Bcl-2 family of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondr ...

, two members of the

Bcl-2 family The Bcl-2 family (TC# 1.A.21) consists of a number of Conserved sequence, evolutionarily-conserved proteins that share Bcl-2 Sequence homology, homology (BH) domains. The Bcl-2 family is most notable for their regulation of apoptosis, a form of pro ...

of evolutionarily-conserved proteins that share Bcl-2 Homology (BH)

domain A domain is a geographic area controlled by a single person or organization. Domain may also refer to: Law and human geography * Demesne, in English common law and other Medieval European contexts, lands directly managed by their holder rather ...

s. First developed as a potential

cancer chemotherapy 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 curat ...

, it was subsequently identified as a

senolytic A senolytic (from the words ''senescence'' and ''-lytic'', "destroying") is among a class of small molecules under basic research to determine if they can selectively induce death of senescent cells and improve health in humans. A goal of this r ...

(a drug that selectively induces

cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as di ...

senescent cells 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 approxim ...

). The Bcl-2 family is most notable for their regulation of

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

, a form of programmed cell death, at the

mitochondrion A mitochondrion () is an organelle found in the cell (biology), cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosine tri ...

; Bcl-2 and Bcl-xL are anti-apoptotic proteins. Because many cancers have mutations in these genes that allow them to survive, scientists began working to develop drugs that would inhibit this pathway in the 1990s. ABT-737 was one of the earliest of a series of drugs developed by

Abbott Laboratories Abbott Laboratories is an American multinational medical devices and health care company with headquarters in Abbott Park, Illinois, in the United States. The company was founded by Chicago physician Wallace Calvin Abbott in 1888 to formulate k ...

(now

Abbvie AbbVie Inc. is an American pharmaceutical company headquartered in North Chicago, Illinois. It is ranked sixth on the list of largest biomedical companies by revenue. In 2023, the company's seat in Forbes Global 2000 was 74, and rank 89 on the ...

) to target this pathway, based on their resolution of the 3D structure of Bcl-xL and studies using high-field solution

nuclear magnetic resonance Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are disturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with a ...

(NMR) that revealed how the BH domains of these proteins interacted with their targets. ABT-737 was superior to previous BCL-2 inhibitors given its higher affinity for Bcl-2, Bcl-xL and

Bcl-w Bcl-2-like protein 2 is a 193-amino acid protein that in humans is encoded by the ''BCL2L2'' gene on chromosome 14 ( band q11.2-q12). It was originally discovered by Leonie Gibson, Suzanne Cory and colleagues at the Walter and Eliza Hall Instit ...

. ''In vitro'' studies showed that primary cells from patients with B-cell malignancies are sensitive to ABT-737. In animal models, it improved survival, caused tumor regression, and cured a high percentage of mice. In preclinical studies utilizing patient xenografts, ABT-737 showed efficacy for treating lymphoma and other blood cancers. Unfortunately, ABT-737 is not

bioavailable 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%. H ...

after

oral administration 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 ...

, leading to the development of

navitoclax Navitoclax (previously ABT-263) is an experimental orally active anti-cancer drug, which is a Bcl-2 inhibitor similar in action to obatoclax. Mechanism of action Navitoclax inhibits not only Bcl-2, but also Bcl-XL and Bcl-w proteins. Becau ...

(ABT-263) as an orally-available derivative with similar activity on

small cell lung cancer Small-cell carcinoma, also known as oat cell carcinoma, is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointestinal tr ...

(SCLC) cell lines. Navitoclax entered

clinical trials Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

, and showed promise in haematologic cancers, but was stalled when it was found to cause

thrombocytopenia In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coag ...

(severe loss of

platelets Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cyto ...

), which was discovered to be caused by the platelets' requirement for Bcl-xL for survival. Subsequently, it was reported that ABT-737 specifically induces apoptosis in senescent cells ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' and in mouse models.

References

{{reflist 4-Chlorophenyl compounds Piperazines Sulfonamides Drugs developed by AbbVie Thioethers