tcsc5143 A-1210477

A-1210477 is a potent and selective inhibitor of MCL-1, and weakly binds to BCL-2 and BCL-XL, with K_i of 0.45 nM, 132 nM and >660 nM, respectively.

IC50 & Target: Ki: 0.45 nM (MCL-1), 132 nM (BCL-2), >660 nM (BCL-XL)^[1]

In Vitro: A-1210477 (10 μM) reduces the amount of BIM co-immunoprecipitated with MCL-1 antibody, and triggers MCL-1 elevation in a variety of cancer cell lines, including the breast cancer cell line HCC-1806. A-1210477 inhibits MCL-1-NOXA interactions with an IC₅₀ of approximately 1 μM, while having no effect on BCL-2-BIM or BCL-XL-BCL-XS interactions. The NSCLC cell lines H2110 and H23 are sensitive to A-1210477 with cell viability IC₅₀<10 μM, confirming that A-1210477 can kill MCL-1-dependent cell lines^[1]. A-1210477 induces extensive concentration-dependent apoptosis in H929 cells following a brief (4 h) exposure. A-1210477 interacts with MCL-1 with Kd of appr 740 nM. A-1210477 (10 μM) induces extensive mitochondrial fragmentation in a DRP-1-dependent manner^[2]. A-1210477 upregulates MCL-1 expression in BRAF-mutant CRC cells and in the melanoma cell line A375 in a dose-dependent manner. A-1210477 releases BAK from MCL-1 and cobimetinib induces BIM that is required for BAX activation^[3]. A-1210477 (0, 5, 10 and 15 μM) has minimal effect on cell viability but substantially sensitizes resistant BCL2High NHL cell lines to navitoclax^[4].