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

Johannes, Jeffrey W.; Bates, Stephanie; Beigie, Carl; Belmonte, Matthew A.; Breen, John; Cao, Shenggen; Centrella, Paolo A.; Clark, Matthew A.; Cuozzo, John W.; Dumelin, Christoph E.; Ferguson, Andrew D.; Habeshian, Sevan; Hargreaves, David; Joubran, Camil; Kazmirski, Steven; Keefe, Anthony D.; Lamb, Michelle L.; Lan, Haiye; Li, Yunxia; Ma, Hao; Mlynarski, Scott; Packer, Martin J.; Rawlins, Philip B.; 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; Zhao, Qiuying; Zheng, Xiaolan; Hird, Alexander W.

doi:10.1021/acsmedchemlett.6b00464

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

Journal Article · Tue Dec 26 23:00:00 EST 2017 · ACS Medicinal Chemistry Letters

DOI:https://doi.org/10.1021/acsmedchemlett.6b00464· OSTI ID:1506537

^[1]; Bates, Stephanie ^[2]; Beigie, Carl ^[1]; Belmonte, Matthew A. ^[1]; Breen, John ^[1]; Cao, Shenggen ^[3]; Centrella, Paolo A. ^[4]; Clark, Matthew A. ^[4]; Cuozzo, John W. ^[4]; Dumelin, Christoph E. ^[4]; ^[1]; Habeshian, Sevan ^[4]; Hargreaves, David ^[2]; Joubran, Camil ^[1]; Kazmirski, Steven ^[1]; Keefe, Anthony D. ^[4]; ^[1]; Lan, Haiye ^[3]; Li, Yunxia ^[3]; Ma, Hao ^[3] more »

AstraZeneca R&D Boston, Waltham, MA (United States)
AstraZeneca R&D Cambridge Science Park, Cambridge (United Kingdom)
Pharmaron Beijing Co., Beijing (China)
X-Chem Pharmaceuticals, Waltham, MA (United States)
AstraZeneca R&D Alderley Park, Cheshire (United Kingdom)

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 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 26 is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl2 at only 5 µM and Bcl-xL at >99 µM, and induce cleaved caspase 3 in MV4-11 cells with an IC₅₀ of 3 µM after 6 hours

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE

OSTI ID:: 1506537

Journal Information:: ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 2 Vol. 8; ISSN 1948-5875

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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