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Title: Novel mutant-selective EGFR kinase inhibitors against EGFR T790M

Abstract

The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.

Authors:
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  1. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1006040
Resource Type:
Journal Article
Journal Name:
Nature
Additional Journal Information:
Journal Volume: 462; Journal Issue: 12, 2009
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; FUNCTIONALS; GROWTH FACTORS; IN VITRO; LUNGS; MUTANTS; MUTATIONS; NEOPLASMS; PHOSPHOTRANSFERASES; PYRIMIDINES; SCREENS; TOXICITY

Citation Formats

Zhou, Wenjun, Ercan, Dalia, Chen, Liang, Yun, Cai-Hong, Li, Danan, Capelletti, Marzia, Cortot, Alexis B., Chirieac, Lucian, Iacob, Roxana E., Padera, Robert, Engen, John R., Wong, Kwok-Kin, Eck, Michael J., Gray, Nathanael S., Jänne, Pasi A., BWH), NEU), and DFCI). Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. United States: N. p., 2010. Web. doi:10.1038/nature08622.
Zhou, Wenjun, Ercan, Dalia, Chen, Liang, Yun, Cai-Hong, Li, Danan, Capelletti, Marzia, Cortot, Alexis B., Chirieac, Lucian, Iacob, Roxana E., Padera, Robert, Engen, John R., Wong, Kwok-Kin, Eck, Michael J., Gray, Nathanael S., Jänne, Pasi A., BWH), NEU), & DFCI). Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. United States. doi:10.1038/nature08622.
Zhou, Wenjun, Ercan, Dalia, Chen, Liang, Yun, Cai-Hong, Li, Danan, Capelletti, Marzia, Cortot, Alexis B., Chirieac, Lucian, Iacob, Roxana E., Padera, Robert, Engen, John R., Wong, Kwok-Kin, Eck, Michael J., Gray, Nathanael S., Jänne, Pasi A., BWH), NEU), and DFCI). Tue . "Novel mutant-selective EGFR kinase inhibitors against EGFR T790M". United States. doi:10.1038/nature08622.
@article{osti_1006040,
title = {Novel mutant-selective EGFR kinase inhibitors against EGFR T790M},
author = {Zhou, Wenjun and Ercan, Dalia and Chen, Liang and Yun, Cai-Hong and Li, Danan and Capelletti, Marzia and Cortot, Alexis B. and Chirieac, Lucian and Iacob, Roxana E. and Padera, Robert and Engen, John R. and Wong, Kwok-Kin and Eck, Michael J. and Gray, Nathanael S. and Jänne, Pasi A. and BWH) and NEU) and DFCI)},
abstractNote = {The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.},
doi = {10.1038/nature08622},
journal = {Nature},
number = 12, 2009,
volume = 462,
place = {United States},
year = {2010},
month = {1}
}