Mechanism of action: BH3 mimetic inhibitor of the anti-apoptotic protein BCL-2 and BCL-xL

Preclinical pharmacology

AZD4320 is a dual inhibitor of Bcl2 and Bcl-xL with 5 nM  and 4 nM potency respectively in biochemical assays (FRET) and able to induce intrinsic apoptosis in cells with 6h caspase EC50values in the nM range (RS4;11 EC50= 10 nM; Ri-1 EC50= 15 nM, OCI-M1 EC50= 60 nM).

AZD4320 monotherapy caused apoptosis preferentially in hematological cell lines with 13/26 AML and 16/27 DLBCL cell lines showing caspase EC50 values <100 nM.  In solid tumor cell lines, single agent activity was seen with 9/16 small cell lung cancer cell lines.

In mice xenograft studies, AZD4320 caused tumor regressions following i.v. dose in subcutaneous and disseminated models of B-ALL and DLBCL.  Induction of cleaved caspase 3 was detected as soon as 6h after i.v. bolus injection.  AZD4320 also significantly enhanced the antitumor activity of Rituximab and Ibrutinib in in vivo models of DLBCL.”

Suitable for and exclusions

Restricted to preclinical oncology studies (proposals) only.

Additional Information

Publications for this compound

Find out more about this compound by reading related Publications:

Justin Cidado, J Paul Secrist, Francis D. Gibbons, Edward J. Hennessy, Stephanos Ioannidis, Edwin A. Clark.  AZD4320 is a potent, dual Bcl-2/xLinhibitor that rapidly induces apoptosis in preclinical hematologic tumor models [abstract].  In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 311.