Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

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

Johannes, Jeffrey W. , Bates, Stephanie, Beigie, Carl, Belmonte, Matt , Breen, John , Cao, Shenggen , Centrella, Paolo A. , Clark, Matthew A., Cuozzo, John W., Dumelin, Christoph, Ferguson, Andrew, Habeshian, Sevan , Hargreaves, David , Joubran, Camil , Kazmirski, Steven , Keefe, Anthony D. , Lamb, Michelle , Lan, Haiye , Li, Yunxia , Ma, Hao , Mlynarski, Scott , Packer, Martin J., Rawlins, Philip , Robbins, Daniel W. , Shen, Haidong , Sigel, Eric A., Soutter, Holly H. , Su, Nancy , Troast, Dawn M., Wang, Haiyun , Wickson, Kate F. , Wu, Chengyan , 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


Email Alerts

Register with OAK to receive email alerts for saved searches.