Navitoclax

Navitoclax
Names

IUPAC name 4-(4-{[2-(4-Chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-[(4-{[(2R)-4-(4-morpholinyl)-1-(phenylsulfanyl)-2-butanyl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]benzamide
Other names ABT263; ABT-263
Identifiers
CAS Number	923564-51-6
ChemSpider	21864722
Jmol interactive 3D	Image
PubChem	24978538
InChI InChI=1S/C47H55ClF3N5O6S3/c1-46(2)20-18-42(34-8-12-37(48)13-9-34)36(31-46)32-55-22-24-56(25-23-55)39-14-10-35(11-15-39)45(57)53-65(60,61)41-16-17-43(44(30-41)64(58,59)47(49,50)51)52-38(19-21-54-26-28-62-29-27-54)33-63-40-6-4-3-5-7-40/h3-17,30,38,52H,18-29,31-33H2,1-2H3,(H,53,57)/t38-/m1/s1 Key: JLYAXFNOILIKPP-KXQOOQHDSA-N InChI=1/C47H55ClF3N5O6S3/c1-46(2)20-18-42(34-8-12-37(48)13-9-34)36(31-46)32-55-22-24-56(25-23-55)39-14-10-35(11-15-39)45(57)53-65(60,61)41-16-17-43(44(30-41)64(58,59)47(49,50)51)52-38(19-21-54-26-28-62-29-27-54)33-63-40-6-4-3-5-7-40/h3-17,30,38,52H,18-29,31-33H2,1-2H3,(H,53,57)/t38-/m1/s1 Key: JLYAXFNOILIKPP-KXQOOQHDBT
SMILES CC1(CCC(=C(C1)CN2CCN(CC2)C3=CC=C(C=C3)C(=O)NS(=O)(=O)C4=CC(=C(C=C4)N[C@H](CCN5CCOCC5)CSC6=CC=CC=C6)S(=O)(=O)C(F)(F)F)C7=CC=C(C=C7)Cl)C
Properties
Chemical formula	C₄₇H₅₅ClF₃N₅O₆S₃
Molar mass	974.61 g·mol⁻¹
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Navitoclax (previously ABT-263) is an experimental orally active anti-cancer drug, which is similar in action to obatoclax, except that unlike obatoclax, it does not have off-target effects.^[1]^[2]

Mechanism of action

Navitoclax inhibits not only Bcl-2, but also Bcl-X_L and Bcl-w proteins.^[3] Because navitoclax inhibits Bcl-XL, it reduces platelet lifespan, causing thrombocytopenia, and this makes it dose-limiting.

Effects Against Senescent Cells

In animal studies, navitoclax was found to be a senolytic agent, inducing apoptosis in senescent, but not non-senescent cells.^[4] 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.^[5]

Clinical trials

ABT-263 was in clinical trials in 2009.^[6]

References

↑ Gandhi, L., Camidge, D. R., de Oliveira, M. R., Bonomi, P., Gandara, D., Khaira, D., ... & Dive, C. (2011). Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. Journal of clinical oncology, 29(7), 909-916 doi: 10.1200/JCO.2010.31.6208
↑ Leverson, J. D., Phillips, D. C., Mitten, M. J., Boghaert, E. R., Diaz, D., Tahir, S. K., ... & Lowes, K. N. (2015). Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Science translational medicine, 7(279), 279ra40-279ra40. doi:10.1126/scitranslmed.aaa4642
↑ The Bcl-2/Bcl-XL/Bcl-w Inhibitor, Navitoclax, Enhances the Activity of Chemotherapeutic Agents In Vitro and In Vivo
↑ Zhu, Y; Tchkonia, T; Fuhrmann-Stroissnigg, H; Dai, HM; Ling, YY; Stout, MB; Pirtskhalava, T; Giorgadze, N; Johnson, KO; Giles, CB; Wren, JD; Niedernhofer, LJ; Robbins, PD; Kirkland, JL (2015). "Identification of a Novel Senolytic Agent, Navitoclax, Targeting the Bcl-2 Family of Anti-Apoptotic Factors". Aging Cell. doi:10.1111/acel.12445. PMID 26711051.
↑ Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, Luo Y, Wang X, Aykin-Burns N, Krager K, Ponnappan U, Hauer-Jensen M, Meng A, Zhou D (2015). "Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice". Nature Medicine. doi:10.1038/nm.4010. PMID 26657143. Retrieved 2015-12-23.
↑ Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737. Hauck. 2009

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