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

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.

SUBMITTER: Wurz RP 

PROVIDER: S-EPMC4569876 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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

Wurz Ryan P RP   Pettus Liping H LH   Ashton Kate K   Brown James J   Chen Jian Jeffrey JJ   Herberich Brad B   Hong Fang-Tsao FT   Hu-Harrington Essa E   Nguyen Tom T   St Jean David J DJ   Tadesse Seifu S   Bauer David D   Kubryk Michele M   Zhan Jinghui J   Cooke Keegan K   Mitchell Petia P   Andrews Kristin L KL   Hsieh Faye F   Hickman Dean D   Kalyanaraman Nataraj N   Wu Tian T   Reid Darren L DL   Lobenhofer Edward K EK   Andrews Dina A DA   Everds Nancy N   Guzman Roberto R   Parsons Andrew T AT   Hedley Simon J SJ   Tedrow Jason J   Thiel Oliver R OR   Potter Matthew M   Radinsky Robert R   Beltran Pedro J PJ   Tasker Andrew S AS  

ACS medicinal chemistry letters 20150727 9

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-fol  ...[more]

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