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
  • 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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