Jeffrey W. Johannes; Stephanie Bates; Carl Beigie; Matthew A. Belmonte; John Breen; Shenggen Cao; Paolo A. Centrella; Matthew A. Clark; John W. Cuozzo; Christoph E. Dumelin; Andrew D. Ferguson; Sevan Habeshian; David Hargreaves; Camil Joubran; Steven Kazmirski; Anthony D. Keefe; Michelle L. Lamb; Haiye Lan; Yunxia Li; Hao Ma; Scott Mlynarski; Martin J. Packer; Philip B. Rawlins; Daniel W. Robbins; Haidong Shen; Eric A. Sigel; Holly H. Soutter; Nancy Su; Dawn M. Troast; Haiyun Wang; Kate F. Wickson; Chengyan Wu; Ying Zhang; Qiuying Zhao; Xiaolan Zheng; Alexander W. Hird
ACS Med. Chem. Lett., 2017, 8, 239−244
https://doi.org/10.1021/acsmedchemlett.6b00464

Abstract

Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein−ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound 26 is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4−11 cells with an IC50 of 3 μM after 6 h.