Mcl-1 (induced myeloid leukemia cell differentiation protein), a member of the Bcl-2 family, can regulate apoptosis both in inhibition- or promotion-manner. MCL-1 has also been implicated in mediating resistance to a variety of commonly used chemotherapeutic agents, as well as the Bcl-2 family inhibitor such as ABT-737, ABT-263. A-1210477 is a potent MCL-1 inhibitor with Ki value of 0.454 nM (measure by (TR-FRET)-binding assays), versus Ki values of 132 nM and > 660 nM for BCL-2 and BCL-XL. A-1210477 at concentration of 3 or 30 μM for 4 h caused reduction of MCL-1/Bim association in H929 cells, as well as decreased MCL-1/NOXA interaction in HeLa cells at concentration of 1, 3 and 10 μM for 24 h. For A-1210477 behaved akin to BH3-only proteins, A-1210477 triggered MCL-1 elevation in a variety of cell lines as prediction. A-1210477 each killed H929 cells with IC50 values in the low-μM range, but not the RS4;11 cell line known to rely on BCL-2 for survival, suggesting that the action of A-1210477 is MCL-1-dependent. The synergy on cell killing of A-1210477 ranging in 5-20μM with ABT-263 can be observed in hematological and solid tumor cell lines, BxPC-3, EJ-1, H23, and OPM-2[1].
作用机制
A-1210477 may act as BH3 mimetics that can bind to Mcl-1 and sequester its pro-apoptotic counterpart BIM.[1]
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