2. Academic Validation
  3. Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities

Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities

  • J Med Chem. 2008 Sep 11;51(17):5330-41. doi: 10.1021/jm800476q.
Kyoung Soon Kim 1,  Liping Zhang,  Robert Schmidt,  Zhen-Wei Cai,  Donna Wei,  David K Williams,  Louis J Lombardo,  George L Trainor,  Dianlin Xie,  Yaquan Zhang,  Yongmi An,  John S Sack,  John S Tokarski,  Celia Darienzo,  Amrita Kamath,  Punit Marathe,  Yueping Zhang,  Jonathan Lippy,  Robert Jeyaseelan Sr,  Barri Wautlet,  Benjamin Henley,  Johnni Gullo-Brown,  Veeraswamy Manne,  John T Hunt,  Joseph Fargnoli,  Robert M Borzilleri
Affiliations

Affiliation

  • 1 Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research & Development, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. kyoung.kim@bms.com
PMID: 18690676 DOI: 10.1021/jm800476q
Abstract

Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.

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