Biochem/physiol Actions

A-1210477 is a BH3 mimetic that targets MCL-1 with high affinity (Ki = 0.43 nM) and selectivity (Ki >0.66 µM for BCL-2, BCL-XL, BCL-W, and A1), exhibiting little to no activity toward panels of 80 kinases (IC50 >8.5 µM) and 21 GPCRs (IC50 & EC50 >10 µM). A-1210477 selectively inhibits the survival of MCL-1-dependent (IC50 ~4 µM/multiple myeloma H929, 5.3 µM/NSCLC H2110, 7.2 µM/NSCLC H23), but not BCL-2-dependent RS4;11, cultures via apoptosis induction and potentiates BCL-2/BCL-XL inhibitor ABT-263 (Navitoclax) killing in a variety of cancer cell cultures where ABT-263 alone is ineffective. A-1210477 is also shown to cause cellular MCL-1 upregulation, most likely due to blocking MCL-1 interaction with BH3-only proteins such as NOXA and MULE known to mediate MCL-1 ubiquitylation for proteasomal degradation.