Description
A-1331852 is an orally bioavailable Bcl-xL inhibitor that selectively binds Bcl-xL over Bcl-2, Mcl-1, and Bcl-W (K
is = <0.01, 6, 142, and 4 nM, respectively). It inhibits growth of Bcl-xL-dependent MOLT-4, but not Bcl-2-dependent RS4;11, acute lymphocytic leukemia cells
in vitro (EC
50s = 6 and >5,000 nM, respectively). A-1331852 (25 mg/kg twice per day) inhibits tumor growth in a MOLT-4 mouse xenograft model. It also inhibits tumor growth and increases the antitumor activity of docetaxel in MDA-MB-231 LC3 metastatic breast cancer and NCI-H1650 non-small cell lung cancer mouse xenograft models when administered at a dose of 25 mg/kg. A-1331852 also increases venetoclax inhibition of tumor growth in an NCI-H1963.FP5 small cell lung cancer mouse xenograft model.
Uses
A-1331852 is a substituted benzothiazole that can serve as an anti-apoptotic Bcl-xL protein inhibitor and apoptosis-inducing agent useful in the treatment of cancer, immune and autoimmune diseases.
in vitro
a-1331852 was identified as a potent bcl-xl inhibitor demonstrating cellular activity 10- to 50-fold more potent than its analog a-1155463 and the previouly reported bcl-xl inhibitor, navitoclax, respectively. moreover, a-1331852 could selectively disrupt bcl-xl–bim complexes and induce the apoptosis hallmarks in bcl-xl–dependent molt-4 cells with median ic50 values in the low nanomolar range but did not affect mef cells without bak or bax [1].
in vivo
previous animal study found that a-1331852 could demonstrate antitumor efficacy in the molt-4 xenograft model, such as tumor regressions as a single agent. in addition, in the nci-h1963.fp5 xenograft model of sclc, it was found that a-1331852 combined with venetoclax was able to recapitulate the efficacy of navitoclax [1].
IC 50
Bcl-xL: 0.01 nM (Ki); Bcl-W: 4 nM (Ki); Bcl-2: 6 nM (Ki); Mcl-1: 142 nM (Ki)
References
[1] leverson jd et al. exploiting selective bcl-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. sci transl med. 2015 mar 18;7(279):279ra40. doi: 10.1126/scitranslmed.aaa4642.
