Therapeutics: Myeloid leukemia cell differentiation protein (MCL1); B cell lymphoma 2 (BCL-2; BCL2); Bcl-XL

In vitro studies identified a tricyclic indole-based, selective inhibitor of MCL1 that could help treat cancer. Fragment-based drug design, chemical synthesis and in vitro testing of tricyclic 2-indole carboxylic acid analogs identified a lead compound that bound MCL1 with a Ki of 3 nM and bound the related Bcl-2 family proteins, Bcl-XL and BCL-2, with Ki values of 5.2 and 0.77 µM, respectively. In a pulldown assay in lysates of a human chronic myelogenous leukemia (CML) cell line, the lead compound inhibited the interaction between MCL1 and a pro-apoptotic peptide in a dose-dependent manner. Next steps could include testing the lead compound in cancer cell lines and animal models.

Teva Pharmaceutical Industries Ltd. and Hospira Inc. market Synribo omacetaxine mepesuccinate, a small molecule that inhibits synthesis of MCL1 and cyclin D1 (CCND1; BCL1) to treat CML...