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Title: Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation

Journal Article · · Journal of Medicinal Chemistry
DOI:https://doi.org/10.1021/jm501578n· OSTI ID:1168859
 [1];  [2];  [1];  [1];  [1];  [3];  [1];  [4];  [4];  [3];  [4];  [5];  [1];  [6];  [7];  [4];  [7];  [8];  [1];  [4] more »;  [7];  [2];  [2];  [8];  [1] « less
  1. Genentech Inc., South San Francisco, CA (United States). Dept. of Discovery Chemistry
  2. Genentech Inc., South San Francisco, CA (United States). Dept. of Structural Biology
  3. Genentech Inc., South San Francisco, CA (United States). Dept. of Drug Metabolism and Pharmacokinetics
  4. Argenta, Harlow, Essex (United Kingdom). Charles River Early Discovery Facility
  5. Genentech Inc., South San Francisco, CA (United States). Dept. of Biochemical and Cellular Pharmacology
  6. Genentech Inc., South San Francisco, CA (United States). Dept. of Molecular Oncology
  7. Genentech Inc., South San Francisco, CA (United States). Dept. of Biochemical and Cellular Pharmacology
  8. Genentech Inc., South San Francisco, CA (United States). Dept. of Protein Expression
+ Show Author Affiliations

Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. Here in this paper, we describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
Grant/Contract Number:
AC02-05CH11231; 085P1000817; AC02-06CH11357
OSTI ID:
1168859
Journal Information:
Journal of Medicinal Chemistry, Vol. 57, Issue 23; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 47 works
Citation information provided by
Web of Science

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Cited By (10)

Unraveling structural requirements of amino-pyrimidine T790M/L858R double mutant EGFR inhibitors: 2D and 3D QSAR study journal July 2018
Revisiting the molecular mechanism of acquired resistance to reversible tyrosine kinase inhibitors caused by EGFR gatekeeper T790M mutation in non-small-cell lung cancer journal July 2018
Decoding molecular mechanism of inhibitor bindings to CDK2 using molecular dynamics simulations and binding free energy calculations text January 2020
Decoding molecular mechanism of inhibitor bindings to CDK2 using molecular dynamics simulations and binding free energy calculations journal March 2019
Decoding molecular mechanism of inhibitor bindings to CDK2 using molecular dynamics simulations and binding free energy calculations text January 2020
Targeting EGFR L858R/T790M and EGFR L858R/T790M/C797S resistance mutations in NSCLC: Current developments in medicinal chemistry journal January 2018
Gossypol Inhibits Non-small Cell Lung Cancer Cells Proliferation by Targeting EGFRL858R/T790M journal July 2018
Decoding molecular mechanism of inhibitor bindings to CDK2 using molecular dynamics simulations and binding free energy calculations text January 2019
Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions journal September 2016
Acetylation of C/EBPα inhibits its granulopoietic function journal March 2016

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