- C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFRT790M mutant
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The development of specific kinase inhibitors has been a long-standing challenge in chemical biology and drug discovery. We have successfully discovered a series of C5-substituted pyrido[2,3-d]pyrimidin-7-ones as highly specific inhibitors against the clinical resistance-related EGFRT790M mutant. One of the most promising compounds, 9f, tightly binds to the EGFRT790M mutant and strongly inhibits its enzymatic function with an IC50 value of 0.80 nM, and displays an extraordinary target specificity with S(35) and S(10) selectivity scores of 0.005 and 0.000, respectively, in a kinase selectivity profiling study against 456 different kinases at 100 nM. The compound also selectively suppresses the proliferation of EGFRT790M mutated H1975 NSCLC cells with an IC50 value of 2.80 nM, but is significantly less toxic to cells with wild-type EGFR. Compound 9f may serve as a promising lead compound for drug discovery overcoming the acquired resistance of NSCLC patients without adverse toxicities.
- Xu, Tianfeng,Peng, Ting,Ren, Xiaomei,Zhang, Lianwen,Yu, Lei,Luo, Jinfeng,Zhang, Zhang,Tu, Zhengchao,Tong, Linjiang,Huang, Zhaoru,Lu, Xiaoyun,Geng, Meiyu,Xie, Hua,Ding, Jian,Ding, Ke
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p. 1693 - 1697
(2015/09/21)
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- Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors
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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.
- 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.
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p. 987 - 992
(2015/09/22)
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- Substituted 7-Oxo-Pyrido[2,3-d]Pyrimidines and Methods of Use
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The invention encompasses compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions, uses and methods for prophylaxis and treatment of cancer.
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