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

DOI: 10.1021/acsmedchemlett.6b00464 DOI Help

Authors: Jeffrey W. Johannes (AstraZeneca) , Stephanie Bates (AstraZeneca) , Carl Beigie (AstraZeneca) , Matthew A. Belmonte (AstraZeneca) , John Breen (AstraZeneca) , Shenggen Cao (Pharmaron Beijing Co., Ltd) , Paolo A. Centrella (X-Chem Pharmaceuticals) , Matthew A. Clark (X-Chem Pharmaceuticals) , John W. Cuozzo (X-Chem Pharmaceuticals) , Christoph E. Dumelin (X-Chem Pharmaceuticals) , Andrew D. Ferguson (AstraZeneca) , Sevan Habeshian (X-Chem Pharmaceuticals) , David Hargreaves (AstraZeneca) , Camil Joubran (AstraZeneca) , Steven Kazmirski (AstraZeneca) , Anthony D. Keefe (X-Chem Pharmaceuticals) , Michelle L. Lamb (AstraZeneca) , Haiye Lan (Pharmaron Beijing Co., Ltd) , Yunxia Li (Pharmaron Beijing Co., Ltd) , Hao Ma (Pharmaron Beijing Co., Ltd) , Scott Mlynarski (AstraZeneca) , Martin J. Packer (AstraZeneca) , Philip B. Rawlins (AstraZeneca) , Daniel W. Robbins (AstraZeneca) , Haidong Shen (Pharmaron Beijing Co., Ltd) , Eric A. Sigel (X-Chem Pharmaceuticals) , Holly H. Soutter (X-Chem Pharmaceuticals) , Nancy Su (AstraZeneca) , Dawn M. Troast (X-Chem Pharmaceuticals) , Haiyun Wang (AstraZeneca) , Kate F. Wickson (AstraZeneca) , Chengyan Wu (Pharmaron Beijing Co., Ltd) , Ying Zhang (X-Chem Pharmaceuticals) , Qiuying Zhao (Pharmaron Beijing Co., Ltd) , Xiaolan Zheng (AstraZeneca) , Alexander W. Hird (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters , VOL 8 , PAGES 239 - 244

State: Published (Approved)
Published: February 2017

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.

Journal Keywords: macrocycles; Mcl-1; peptides; protein−protein interactions

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography