Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax)

The anti-apoptotic protein Mcl-1 is a key regulator of Cancer cell survival and a known resistance factor for small-molecule Bcl-2 Family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption of high-affinity protein-protein interactions, and therefore designing small molecules potent enough to inhibit Mcl-1 in cells has proven extremely challenging. Here, we describe a series of indole-2-carboxylic acids, exemplified by the compound A-1210477, that bind to Mcl-1 selectively and with sufficient affinity to disrupt MCL-1-BIM complexes in living cells. A-1210477 induces the hallmarks of intrinsic Apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung Cancer cell lines demonstrated to be Mcl-1 dependent by BH3 profiling or siRNA rescue experiments. As predicted, A-1210477 synergizes with the Bcl-2/Bcl-xL Inhibitor navitoclax to kill a variety of Cancer cell lines. This work represents the first description of small-molecule Mcl-1 inhibitors with sufficient potency to induce clear on-target cellular activity. It also demonstrates the utility of these molecules as chemical tools for dissecting the basic biology of Mcl-1 and the promise of small-molecule Mcl-1 inhibitors as potential therapeutics for the treatment of Cancer.