Scaffold hopping from indoles to indazoles yields dual MCL-1/BCL-2 inhibitors from MCL-1 selective leads.

Overexpression of the anti-apoptotic BCL-2 proteins is associated with the development and progression of a range of cancers. Venetoclax, an FDA-approved BCL-2 inhibitor, is fast becoming the standard-of-care for acute myeloid leukemia and chronic lymphocytic leukemia. However, the median survival offered by venetoclax is only 18 months (as part of a combination therapy regimen), and one of the primary culprits for this is the concomitant upregulation of sister anti-apoptotic proteins, in particular MCL-1 (and BCL-xL), which provides an escape route that manifests as venetoclax resistance.

Discovery of Mcl-1 inhibitors based on a thiazolidine-2,4-dione scaffold.

Inspired by a rhodanine-based dual inhibitor of Bcl-x and Mcl-1, a focused library of analogues was prepared wherein the rhodanine core was replaced with a less promiscuous thiazolidine-2,4-dione scaffold. Compounds were initially evaluated for their abilities to inhibit Mcl-1. The most potent compound 12b inhibited Mcl-1 with a K of 155 nM.