1610733-10-2Relevant academic research and scientific papers
Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors
Wurz, Ryan P.,Pettus, Liping H.,Ashton, Kate,Brown, James,Chen, Jian Jeffrey,Herberich, Brad,Hong, Fang-Tsao,Hu-Harrington, Essa,Nguyen, Tom,St. Jean, David J.,Tadesse, Seifu,Bauer, David,Kubryk, Michele,Zhan, Jinghui,Cooke, Keegan,Mitchell, Petia,Andrews, Kristin L.,Hsieh, Faye,Hickman, Dean,Kalyanaraman, Nataraj,Wu, Tian,Reid, Darren L.,Lobenhofer, Edward K.,Andrews, Dina A.,Everds, Nancy,Guzman, Roberto,Parsons, Andrew T.,Hedley, Simon J.,Tedrow, Jason,Thiel, Oliver R.,Potter, Matthew,Radinsky, Robert,Beltran, Pedro J.,Tasker, Andrew S.
supporting information, p. 987 - 992 (2015/09/22)
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.
Substituted 7-Oxo-Pyrido[2,3-d]Pyrimidines and Methods of Use
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Paragraph 0223; 0226; 0227; 0229, (2014/09/16)
The invention encompasses compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions, uses and methods for prophylaxis and treatment of cancer.
