De novo design, synthesis and evaluation of benzylpiperazine derivatives as highly selective binders of Mcl-1.

Considerable efforts have been made to the development of small-molecule inhibitors of antiapoptotic B-cell lymphoma 2 (Bcl-2) family proteins (such as Bcl-2, Bcl-xL , and Mcl-1) as a new class of anticancer therapies. Unlike general inhibitors of the entire family, selective inhibitors of each member protein can hopefully reduce the adverse side effects in chemotherapy treatments of cancers overexpressing different Bcl-2 family proteins. In this study, we designed four series of benzylpiperazine derivatives as plausible Bcl-2 inhibitors based on the outcomes of a computational algorithm. A total of 81 compounds were synthesized, and their binding affinities to Bcl-2, Bcl-xL , and Mcl-1 measured. Encouragingly, 22 compounds exhibited binding affinities in the micromolar range (Ki <20 μM) to at least one target protein. Moreover, some compounds were observed to be highly selective binders to Mcl-1 with no detectable binding to Bcl-2 or Bcl-xL , among which the most potent one has a Ki value of 0.18 μM for Mcl-1. Binding modes of four selected compounds to Mcl-1 and Bcl-xL were derived through molecular docking and molecular dynamics simulations. It seems that the binding affinity and selectivity of these compounds can be reasonably interpreted with these models. Our study demonstrated the possibility for obtaining selective Mcl-1 inhibitors with relatively simple chemical scaffolds. The active compounds identified by us could be used as lead compounds for developing even more potent selective Mcl-1 inhibitors with potential pharmaceutical applications.