Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin.

By taking advantage of the apoptosis-inducing capacity of artemisinin derivatives, we developed several series of compounds by merging the basic structural elements of the natural product artemisinin into the P2 interaction pocket of the clinically prescribed Bcl-2 inhibitor venetoclax. Most of the new compounds displayed improved biochemical potency against Bcl-2 and high selectivity over Bcl-xL. Specifically, compounds 27c and 34c were found to be the most potent with IC50 values less than 2.0 nM. Unfortunately, these compounds only showed moderate antiproliferative effects against Bcl-2 dependent cells. Though further structural optimization is needed to improve the cellular absorptive permeability, the current approach represents an alternative strategy to develop novel Bcl-2 inhibitors with greater selectivity over Bcl-xL, which is related to the off-target adverse effects of venetoclax.