2. Academic Validation
  3. Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors

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

  • ACS Med Chem Lett. 2016 Dec 27;8(2):239-244. doi: 10.1021/acsmedchemlett.6b00464.
Jeffrey W Johannes 1,  Stephanie Bates 2,  Carl Beigie 1,  Matthew A Belmonte 1,  John Breen 1,  Shenggen Cao 3,  Paolo A Centrella 4,  Matthew A Clark 4,  John W Cuozzo 4,  Christoph E Dumelin 4,  Andrew D Ferguson 1,  Sevan Habeshian 4,  David Hargreaves 2,  Camil Joubran 1,  Steven Kazmirski 1,  Anthony D Keefe 4,  Michelle L Lamb 1,  Haiye Lan 3,  Yunxia Li 3,  Hao Ma 3,  Scott Mlynarski 1,  Martin J Packer 5,  Philip B Rawlins 2,  Daniel W Robbins 1,  Haidong Shen 3,  Eric A Sigel 4,  Holly H Soutter 4,  Nancy Su 1,  Dawn M Troast 4,  Haiyun Wang 1,  Kate F Wickson 2,  Chengyan Wu 3,  Ying Zhang 4,  Qiuying Zhao 3,  Xiaolan Zheng 1,  Alexander W Hird 1
Affiliations

Affiliations

  • 1 AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • 2 AstraZeneca R&D Cambridge Science Park , Unit 310 Darwin Building, Cambridge CB4 0WG, United Kingdom.
  • 3 Pharmaron Beijing Co., Ltd. 6 Taihe Road BDA, Beijing 100176 P. R. China.
  • 4 X-Chem Pharmaceuticals , 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • 5 AstraZeneca R&D Alderley Park , Macclesfield, Cheshire SK10 4TG, United Kingdom.
PMID: 28197319 DOI: 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.

Keywords

Mcl-1; macrocycles; peptides; protein−protein interactions.

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