Discovery and Optimization of the First ATP Competitive Type-III c-MET Inhibitor

  • J Med Chem. 2023 Jul 13;66(13):8782-8807. doi: 10.1021/acs.jmedchem.3c00401.
Iacovos N Michaelides  1 ,  Gavin W Collie  1 ,  Ulf Börjesson  2 ,  Christina Vasalou  3 ,  Omar Alkhatib  1 ,  Louise Barlind  2 ,  Tony Cheung  4 ,  Ian L Dale  1 ,  Kevin J Embrey  1 ,  Edward J Hennessy  5 ,  Puneet Khurana  1 ,  Cheryl M Koh  4 ,  Michelle L Lamb  6 ,  Jianming Liu  2 ,  Thomas A Moss  7 ,  Daniel J O'Neill  1 ,  Christopher Phillips  1 ,  Joseph Shaw  1 ,  Arjan Snijder  2 ,  R Ian Storer  1 ,  Christopher J Stubbs  1 ,  Fujin Han  8 ,  Chengzhi Li  8 ,  Jingchuan Qiao  8 ,  Dong-Qing Sun  8 ,  Jingwen Wang  8 ,  Peng Wang  8 ,  Wenzhen Yang  8
Affiliations
  • 1. Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom.
  • 2. Discovery Sciences, R&D, AstraZeneca, 43183 Mölndal, Sweden.
  • 3. DMPK, Oncology R&D, AstraZeneca, Boston, Waltham, Massachusetts 02451, United States.
  • 4. Bioscience, Oncology R&D, AstraZeneca, Boston, Waltham, Massachusetts 02451, United States.
  • 5. Medicinal Chemistry, Oncology R&D, AstraZeneca, Boston, Waltham, Massachusetts 02451, United States.
  • 6. Computational Chemistry, Oncology R&D, AstraZeneca, Boston, Waltham, Massachusetts 02451, United States.
  • 7. Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge, CB4 0WG, United Kingdom.
  • 8. Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, 100176 Beijing, People's Republic of China.
PMID: 37343272 DOI: 10.1021/acs.jmedchem.3c00401
Abstract

Recent clinical reports have highlighted the need for wild-type (WT) and mutant dual inhibitors of c-MET kinase for the treatment of Cancer. We report herein a novel chemical series of ATP competitive type-III inhibitors of WT and D1228V mutant c-MET. Using a combination of structure-based drug design and computational analyses, ligand 2 was optimized to a highly selective chemical series with nanomolar activities in biochemical and cellular settings. Representatives of the series demonstrate excellent pharmacokinetic profiles in rat in vivo studies with promising free-brain exposures, paving the way for the design of brain permeable drugs for the treatment of c-MET driven cancers.

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