2. Academic Validation
  3. Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity

Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity

  • J Med Chem. 2016 Mar 24;59(6):2328-42. doi: 10.1021/acs.jmedchem.5b01716.
Alessandro A Boezio 1,  Katrina W Copeland 1,  Karen Rex 2,  Brian K Albrecht 1,  David Bauer 1,  Steven F Bellon 1,  Christiane Boezio 1,  Martin A Broome 2,  Deborah Choquette 1,  Angela Coxon 2,  Isabelle Dussault 2,  Satoko Hirai 1,  Richard Lewis 1,  Min-Hwa Jasmine Lin 1,  Julia Lohman 1,  Jingzhou Liu 1,  Emily A Peterson 1,  Michele Potashman 1,  Roman Shimanovich 1,  Yohannes Teffera 1,  Douglas A Whittington 1,  Karina R Vaida 1,  Jean-Christophe Harmange 1
Affiliations

Affiliations

  • 1 Amgen Incorporated , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 2 Amgen Incorporated , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
PMID: 26812066 DOI: 10.1021/acs.jmedchem.5b01716
Abstract

Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition factor (MET) has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of compound 23 (AMG 337), which demonstrates nanomolar inhibition of MET kinase activity, desirable preclinical pharmacokinetics, significant inhibition of MET phosphorylation in mice, and robust tumor growth inhibition in a MET-dependent mouse efficacy model.

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