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Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors

Johannes, Jeffrey W. and Bates, Stephanie and Beigie, Carl and Belmonte, Matt and Breen, John and Cao, Shenggen and Centrella, Paolo A. and Clark, Matthew A. and Cuozzo, John W. and Dumelin, Christoph and Ferguson, Andrew and Habeshian, Sevan and Hargreaves, David and Joubran, Camil and Kazmirski, Steven and Keefe, Anthony D. and Lamb, Michelle and Lan, Haiye and Li, Yunxia and Ma, Hao and Mlynarski, Scott and Packer, Martin J. and Rawlins, Philip and Robbins, Daniel W. and Shen, Haidong and Sigel, Eric A. and Soutter, Holly H. and Su, Nancy and Troast, Dawn M. and Wang, Haiyun and Wickson, Kate F. and Wu, Chengyan and Zhang, Ying and Hird, Alex (2017) Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors. ACS Medicinal Chemistry Letters. ISSN 1948-58751948-5875


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 ß-turn conformation, so 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 residue 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 29 is a <3 nM Mcl-1 inhibitor, selective against Bcl-2 and Bcl-xL, and is able to induce cleaved caspase 3 in MV4-11 cells with an IC50 of 3 µM after 6 hours of compound treatment.

Item Type: Article
Date Deposited: 12 Jan 2017 00:45
Last Modified: 12 Jan 2017 00:45


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