Chemical Properties
Pale Yellow Solid
Uses
A novel inhibitor of antiapoptotic BCL-2 proteins; a new promising anticancer drug candidate.
Uses
ABT-263 (Navitoclax) is a potent inhibitor of Bcl-xL, Bcl-2 and Bcl-w with Ki of ≤ 0.5 nM, ≤1 nM and ≤ 1 nM, respectively.
Definition
ChEBI: Navitoclax is a N-sulfonylcarboxamide resulting from the formal condensation of the carboxy group of 4-{4-[(4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro[biphenyl]-2-yl)methyl]piperazin-1-yl}benzoic acid with the amino group of 4-{[(2R)-4-(morpholin-4-yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-[(trifluoromethyl)sulfonyl]benzenesulfonamide. It is a BH3-mimetic drug which targets the anti-apoptotic B-cell lymphoma-2 (BCL-2) family proteins, including BCL-2, BCL-xL, and BCL-w, and induces apoptosis in cancer cells. Currently under clinical investigation as treatment for solid tumors and hematologic malignancies. It has a role as a B-cell lymphoma 2 inhibitor, an apoptosis inducer and an antineoplastic agent. It is a member of piperazines, a member of monochlorobenzenes, a member of morpholines, an aryl sulfide, a N-sulfonylcarboxamide, a sulfone, an organofluorine compound, a secondary amino compound and a tertiary amino compound.
Mechanism of action
ABT‐263 exerts its senolytic activity in senescent tumor cells by inhibiting BCL‐XL's interaction with BAX. ABT‐263 is a BH3 mimetic that inhibits anti‐apoptotic BCL‐2 family proteins by impeding their ability to bind pro‐apoptotic proteins, such as BAK and BAX. BCL‐2 and BCL‐XL are the primary targets of ABT‐263 in cancer cells.
Pharmacokinetics
The pharmacokinetic profile of ABT-263 is characterized by low plasma clearance values and low volumes of distribution in mice, rats, dogs, and monkeys, with plasma elimination half-lives after i.v. Dose of 4.6 to 8.4 hours. Bioavailability after oral gavage was ～20% in all four species. Due to its low aqueous solubility, ABT-263 displays a prolonged dissolution rate-limited oral absorption. P.o. administration in lipid-based formulations, in which the compound is significantly more soluble, yields enhanced absorption with bioavailability near 50% and an oral elimination half-life of 8.9 hours in dogs[5].
storage
Desiccate at -20°C
References
1) Tse?et al.?(2008),?ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor; Cancer Res.,?68?3421
2) Vogler?et al.?(2009),?Bcl-2 inhibitors: small molecules with a big impact on cancer therapy; Cell Death Differ.,?16?360
3) Yamaguchi?et al.?(2011),?Efficient elimination of cancer cells by deoxyglucose-ABT-263/737 combination therapy; PLoS ONE,?6(9)?e24102
4) Zhu?et al.?(2016),?Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors; Aging Cell,?15?428
