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Title: Structural basis of mutant-selectivity and drug-resistance related to CO-1686

Journal Article · · Oncotarget
 [1];  [1];  [1];  [1];  [2];  [1]
  1. Peking Univ. Health Science Center, Beijing (China)
  2. Harvard Medical School, Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States)
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Non-small-cell lung cancers (NSCLCs) caused by activating mutations in the kinase domain of epidermal growth factor receptor (EGFR) initially respond to first-generation reversible drugs gefitinib and erlotinib. However, clinical efficacy is limited due to the development of drug-resistance that in more than half of the cases are driven by the secondary T790M mutation. CO-1686 is one of the third generation irreversible inhibitors that inhibits EGFR activating mutants, including those with concurrent T790M, while avoiding the off-target toxicity owing to inhibition of wild-type EGFR in treating EGFR mutation-positive NSCLCs. Despite the remarkable success, the experimentally determined structure of this agent in complex with EGFR T790M remains unknown. In this study, we determined crystal structures of EGFR T790M or L858R mutants covalently bound by CO-1686. Based on these structural data, we can explain why CO-1686 irreversibly inhibits EGFR and selectively prefers T790M, which may help improving this or similar compounds, and explain why EGFR L718Q and L844V mutations incur resistance to this agent.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Natural Science Foundation of China (NSFC); Ministry of Science and Technology of China
Grant/Contract Number:
31270769; NCET-12-0013
OSTI ID:
1570754
Journal Information:
Oncotarget, Vol. 8, Issue 32; ISSN 1949-2553
Publisher:
Impact JournalsCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 18 works
Citation information provided by
Web of Science

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Cited By (3)

Structural insights into drug development strategy targeting EGFR T790M/C797S journal January 2018
L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib journal January 2018
How Different Substitution Positions of F, Cl Atoms in Benzene Ring of 5-Methylpyrimidine Pyridine Derivatives Affect the Inhibition Ability of EGFRL858R/T790M/C797S Inhibitors: A Molecular Dynamics Simulation Study journal February 2020

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Related Subjects

60 APPLIED LIFE SCIENCES
NSCLC
EGFR kinase
T790M
CO-1686
structural pharmacology