Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors

Ryan P. Wurz, Liping H. Pettus, Kate Ashton, James Brown, Jian Jeffrey Chen, Brad Herberich, Fang Tsao Hong, Essa Hu-Harrington, Tom Nguyen, David J. St. Jean, Seifu Tadesse, David Bauer, Michele Kubryk, Jinghui Zhan, Keegan Cooke, Petia Mitchell, Kristin L. Andrews, Faye Hsieh, Dean Hickman, Nataraj KalyanaramanTian Wu, Darren L. Reid, Edward K. Lobenhofer, Dina A. Andrews, Nancy Everds, Roberto Guzman, Andrew T. Parsons, Simon J. Hedley, Jason Tedrow, Oliver R. Thiel, Matthew Potter, Robert Radinsky, Pedro J. Beltran, Andrew S. Tasker

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


In nonsmall cell lung cancer (NSCLC), the threonine790-methionine790 (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido[2,3-d]pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound 24 which potently inhibits gefitinib-resistant EGFRL858R,T790M with 100-fold selectivity over wild-type EGFR. Compound 24 displays strong antiproliferative activity against the H1975 nonsmall cell lung cancer cell line, the first line mutant HCC827 cell line, and promising antitumor activity in an EGFRL858R,T790M driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR.

Original languageEnglish
Pages (from-to)987-992
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number9
StatePublished - 10 Sep 2015
Externally publishedYes


  • EGFR
  • EGFR T790M mutant
  • Epidermal growth factor receptor
  • irreversible inhibitor
  • kinase inhibitor
  • nonsmall cell lung cancer


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