Navitoclax (previously ABT-263) is an experimental orally active anti-

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

drug, which is a

Bcl-2 inhibitor Bcl-2 (B-cell lymphoma 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 that regulate cell death (apoptosis), by either inhibiting (anti-apopt ...

similar in action to obatoclax.

Mechanism of action

Navitoclax inhibits not only

Bcl-2 Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosi ...

, but also Bcl-X_L 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 Institut ...

proteins. Because navitoclax inhibits Bcl-XL, it reduces platelet lifespan, causing

thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients a ...

, and this makes it dose-limiting.

Effects against senescent cells

In animal studies, navitoclax was found to be 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 ...

agent, inducing apoptosis in

senescent Senescence () or biological aging is the gradual deterioration of functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence inv ...

, but not non-senescent cells. Oral administration of ABT263 to either sublethally irradiated or normally aged mice reduced senescent cells, including senescent bone marrow hematopoietic stem cells and senescent muscle stem cells. This depletion mitigated total-body irradiation-induced premature aging of the hematopoietic system and rejuvenated the aged hematopoietic stem cells and muscle stem cells in normally aged mice. On September 19, 2018, an article was published in Nature about using this drug to kill senescent glial cells in mice. The drug had a protective effect against memory loss in mice genetically engineered to simulate Alzheimer's Disease.

Clinical trials

ABT-263 was studied in 2009. In January 2017, Navitoclax was evaluated as a combination treatment against solid tumors together with

trametinib Trametinib, sold under the brand name Mekinist among others, is an anticancer medication used for the treatment of melanoma. It is a MEK inhibitor drug with anti-cancer activity. It inhibits MEK1 and MEK2. Trametinib had good results for metas ...

in a clinical trial sponsored by the

National Cancer Institute The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...

Antisclerotic

Not directly related to cancer, rather as a therapy for

scleroderma Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. The disease can be either localized to the skin or involve other organs, as well. Symptoms may include areas ...

, Navitocla
appeared to reduce existing fibrosis
through inducing apoptosis of

myofibroblasts A myofibroblast is a cell phenotype that was first described as being in a state between a fibroblast and a smooth muscle cell. Structure Myofibroblasts are contractile web-like fusiform cells that are identifiable by their expression of α-sm ...

. Further research is required to elucidate the exact mechanisms and confirm studies.

References

{{reflist Experimental cancer drugs Trifluoromethyl compounds Sulfonamides 4-Morpholinyl compunds Chloroarenes Phenylpiperazines Cyclohexenes