Virtual screening for potential inhibitors of Mcl-1 conformations sampled by normal modes, molecular dynamics, and nuclear magnetic resonance

Glantz-Gashai, Yitav; Meirson, Tomer; Reuveni, Eli; Samson, Abraham O

Anti-apoptotic proteins are commonly overexpressed in a number of human cancers where they foster the survival of tumor cells. To inhibit anti-apoptosis (ie, promote apoptosis) and interfere with tumor cell survival, several small-molecule drugs that mimic pro-apoptotic BH3 proteins were developed. 3 The BH3-mimetics include ABT-737 4 and its orally available derivative ABT-263. 5 These BH3-mimetics bind selectively to Bcl-2, Bcl-xL, and Bcl-w and interfere with cell survival; however, they do not bind to Mcl-1 and some cancers cannot be treated by these compounds alone. To complicate things further, upregulation of Mcl-1 is a key factor in the development of resistance to ABT-737 and ABT-263. 2 Thus, there is an unmet need to design ligands, and in particular new small molecules, that inhibit Mcl-1. 6 Mcl-1 is a major cancer target, and Mcl-1 overexpression is often encountered in human cancer. 7, 8 Mcl-1 overexpression has been reported in breast cancer, 9 lung cancer, 10 prostate cancer, 11 pancreatic cancer, 12 cervical and ovarian cancers, 13 and leukemia. 14 Mcl-1 overexpression leads to resistance against Bcl-2-selective inhibitors and other smallmolecule drugs used in chemotherapy. 15 Remarkably, in vitro inhibition of Mcl-1 overexpression through RNA silencing inhibits tumor growth 16 and abolishes chemoresistance. 17 As such, Mcl-1 represents a promising cancer target.