A-1331852

A-1331852 is an orally available BCL-XL selective inhibitor with a Ki of less than 10 pM.

Signaling Pathways >> Apoptosis >> Bcl-2 Family

Research Areas >> Cancer

Bcl-xL:0.01 nM (Ki)

Bcl-W:4 nM (Ki)

Bcl-2:6 nM (Ki)

Mcl-1:142 nM (Ki)

A-1331852 selectively disrupts BCL-XL–BIM complexes and induces the hallmarks of apoptosis in BCL-XL–dependent Molt-4 cells with IC50s in the low nanomolar range but does not affect MEF cells lacking BAK or BAX. In CellTiter-Glo cell viability assay, A-1331852 inhibits NCI-H847, NCI-H1417, SET-2, HEL, OCI-M2 with EC50 values of 3, 7, 80, 120 and 100 nM[1].

A-1331852 demonstrates antitumor efficacy in the Molt-4 xenograft model, inducing tumor regressions as a single agent. Additionally, A-1331852 combines with venetoclax to recapitulate the efficacy of navitoclax in the NCI-H1963.FP5 xenograft model of SCLC. A-1331852 significantly inhibits tumor growth in seven subcutaneous xenograft models of solid tumors, including breast cancer, NSCLC, and ovarian cancer[1].

SCLC and AML cell lines are incubated with increasing concentrations of navitoclax, venetoclax, or A-1155463 for 48 hours before assessing cell viability. Cell killing EC50 values are calculated[1].

Mice: The growth inhibition of established tumors in SCID-bg mice is studied. A-1331852 is administered orally daily for 14 days at 25 mg/kg and docetaxel is administered intravenously at 7.5 mg/kg. The change of tumor volume is monitored daily[1].

[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.

Venetoclax (ABT-199) | ABT-263 | S63845 | ABT-737 | Obatoclax Mesylate | A-1210477 | A-1155463 | WEHI-539 hydrochloride | Bax inhibitor peptide V5 | FX 1 | Gambogic Acid | TW-37 | UMI-77 | Acetate gossypol | HA14-1