| Literature DB >> 26396685 |
Ryan P Wurz1, Liping H Pettus1, Kate Ashton1, James Brown1, Jian Jeffrey Chen1, Brad Herberich1, Fang-Tsao Hong1, Essa Hu-Harrington1, Tom Nguyen1, David J St Jean1, Seifu Tadesse1, David Bauer2, Michele Kubryk2, Jinghui Zhan1, Keegan Cooke1, Petia Mitchell1, Kristin L Andrews1, Faye Hsieh1, Dean Hickman1, Nataraj Kalyanaraman1, Tian Wu1, Darren L Reid1, Edward K Lobenhofer1, Dina A Andrews1, Nancy Everds1, Roberto Guzman1, Andrew T Parsons2, Simon J Hedley1, Jason Tedrow1, Oliver R Thiel1, Matthew Potter2, Robert Radinsky1, Pedro J Beltran1, Andrew S Tasker1.
Abstract
In nonsmall cell lung cancer (NSCLC), the threonine(790)-methionine(790) (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 EGFR(L858R,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 EGFR(L858R,T790M) driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR.Entities:
Keywords: EGFR; EGFR T790M mutant; Epidermal growth factor receptor; irreversible inhibitor; kinase inhibitor; nonsmall cell lung cancer
Year: 2015 PMID： 26396685 PMCID： PMC4569876 DOI： 10.1021/acsmedchemlett.5b00193
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345