2. Academic Validation
  3. Discovery and Optimization of the First ATP Competitive Type-III c-MET Inhibitor

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

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.

Figures
Products