Navitoclax

Navitoclax (previously ABT-263) is an experimental orally active anti-cancer drug, which is a Bcl-2 inhibitor similar in action to obatoclax.[1][2]

Navitoclax
Names
Preferred IUPAC name
4-(4-{[2-(4-Chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-(trifluoromethanesulfonyl)benzene-1-sulfonyl)benzamide
Other names
ABT263; ABT-263
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
UNII
  • 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
  • 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
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

Mechanism of action

Navitoclax inhibits not only Bcl-2, but also Bcl-XL 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]

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.[6]

Clinical trials

ABT-263 was studied in 2009.[7] In January 2017, Navitoclax was evaluated as a combination treatment against solid tumors together with trametinib in a clinical trial sponsored by the National Cancer Institute.[8]

Antisclerotic

Not directly related to cancer, rather as a therapy for scleroderma, Navitoclax appeared to reduce existing fibrosis through inducing apoptosis of myofibroblasts. Further research is required to elucidate the exact mechanisms and confirm studies.

References
  1. Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D, Hann CL, McKeegan EM, Litvinovich E, Hemken PM, Dive C, Enschede SH, Nolan C, Chiu YL, Busman T, Xiong H, Krivoshik AP, Humerickhouse R, Shapiro GI, Rudin CM (March 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): 909–16. doi:10.1200/JCO.2010.31.6208. PMC 4668282. PMID 21282543.
  2. Leverson JD, Phillips DC, Mitten MJ, Boghaert ER, Diaz D, Tahir SK, et al. (March 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. doi:10.1126/scitranslmed.aaa4642. PMID 25787766. S2CID 206686917.
  3. Chen, J.; Jin, S.; Abraham, V.; Huang, X.; Liu, B.; Mitten, M. J.; Nimmer, P.; Lin, X.; Smith, M.; Shen, Y.; Shoemaker, A. R.; Tahir, S. K.; Zhang, H.; Ackler, S. L.; Rosenberg, S. H.; Maecker, H.; Sampath, D.; Leverson, J. D.; Tse, C.; Elmore, S. W. (2011). "The Bcl-2/Bcl-XL/Bcl-w Inhibitor, Navitoclax, Enhances the Activity of Chemotherapeutic Agents In Vitro and In Vivo". Molecular Cancer Therapeutics. Mol Cancer Ther. 2011 Dec;10(12):2340-9. doi: 10.1158/1535-7163.MCT-11-0415. Epub 2011 Sep 13. 10 (12): 2340–9. doi:10.1158/1535-7163.MCT-11-0415. PMID 21914853.
  4. Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, et al. (June 2016). "Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors". Aging Cell. 15 (3): 428–35. doi:10.1111/acel.12445. PMC 4854923. PMID 26711051.
  5. 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 (January 2016). "Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice". Nature Medicine. 22 (1): 78–83. doi:10.1038/nm.4010. PMC 4762215. PMID 26657143.
  6. Bussian, Tyler J.; Aziz, Asef; Meyer, Charlton F.; Swenson, Barbara L.; van Deursen, Jan M.; Baker, Darren J. (October 2018). "Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline". Nature. 562 (7728): 578–582. doi:10.1038/s41586-018-0543-y. ISSN 1476-4687. PMC 6206507. PMID 30232451.
  7. Hauck P, Chao BH, Litz J, Krystal GW (April 2009). "Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737". Molecular Cancer Therapeutics. 8 (4): 883–92. doi:10.1158/1535-7163.MCT-08-1118. PMID 19372561.
  8. National Cancer Institute (sponsor), Corcoran R. "Trametinib and Navitoclax in Treating Patients With Advanced or Metastatic Solid Tumors". ClinicalTrials.gov. National Institutes of Health. Retrieved 24 June 2017. ClinicalTrials.gov Identifier: NCT02079740
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