Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation
Abstract
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.
- Authors:
-
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- Genentech Inc., South San Francisco, CA (United States). Dept. of Discovery Chemistry
- Genentech Inc., South San Francisco, CA (United States). Dept. of Structural Biology
- Genentech Inc., South San Francisco, CA (United States). Dept. of Drug Metabolism and Pharmacokinetics
- Argenta, Harlow, Essex (United Kingdom). Charles River Early Discovery Facility
- Genentech Inc., South San Francisco, CA (United States). Dept. of Biochemical and Cellular Pharmacology
- Genentech Inc., South San Francisco, CA (United States). Dept. of Molecular Oncology
- Genentech Inc., South San Francisco, CA (United States). Dept. of Biochemical and Cellular Pharmacology
- Genentech Inc., South San Francisco, CA (United States). Dept. of Protein Expression
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
- OSTI Identifier:
- 1168859
- Grant/Contract Number:
- AC02-05CH11231; 085P1000817; AC02-06CH11357
- Resource Type:
- Journal Article: Accepted Manuscript
- Journal Name:
- Journal of Medicinal Chemistry
- Additional Journal Information:
- Journal Volume: 57; Journal Issue: 23; Journal ID: ISSN 0022-2623
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES
Citation Formats
Hanan, Emily J., Eigenbrot, Charles, Bryan, Marian C., Burdick, Daniel J., Chan, Bryan K., Chen, Yuan, Dotson, Jennafer, Heald, Robert A., Jackson, Philip S., La, Hank, Lainchbury, Michael D., Malek, Shiva, Purkey, Hans E., Schaefer, Gabriele, Schmidt, Stephen, Seward, Eileen M., Sideris, Steve, Tam, Christine, Wang, Shumei, Yeap, Siew Kuen, Yen, Ivana, Yin, Jianping, Yu, Christine, Zilberleyb, Inna, and Heffron, Timothy P. Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation. United States: N. p., 2014.
Web. doi:10.1021/jm501578n.
Hanan, Emily J., Eigenbrot, Charles, Bryan, Marian C., Burdick, Daniel J., Chan, Bryan K., Chen, Yuan, Dotson, Jennafer, Heald, Robert A., Jackson, Philip S., La, Hank, Lainchbury, Michael D., Malek, Shiva, Purkey, Hans E., Schaefer, Gabriele, Schmidt, Stephen, Seward, Eileen M., Sideris, Steve, Tam, Christine, Wang, Shumei, Yeap, Siew Kuen, Yen, Ivana, Yin, Jianping, Yu, Christine, Zilberleyb, Inna, & Heffron, Timothy P. Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation. United States. https://doi.org/10.1021/jm501578n
Hanan, Emily J., Eigenbrot, Charles, Bryan, Marian C., Burdick, Daniel J., Chan, Bryan K., Chen, Yuan, Dotson, Jennafer, Heald, Robert A., Jackson, Philip S., La, Hank, Lainchbury, Michael D., Malek, Shiva, Purkey, Hans E., Schaefer, Gabriele, Schmidt, Stephen, Seward, Eileen M., Sideris, Steve, Tam, Christine, Wang, Shumei, Yeap, Siew Kuen, Yen, Ivana, Yin, Jianping, Yu, Christine, Zilberleyb, Inna, and Heffron, Timothy P. 2014.
"Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation". United States. https://doi.org/10.1021/jm501578n. https://www.osti.gov/servlets/purl/1168859.
@article{osti_1168859,
title = {Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation},
author = {Hanan, Emily J. and Eigenbrot, Charles and Bryan, Marian C. and Burdick, Daniel J. and Chan, Bryan K. and Chen, Yuan and Dotson, Jennafer and Heald, Robert A. and Jackson, Philip S. and La, Hank and Lainchbury, Michael D. and Malek, Shiva and Purkey, Hans E. and Schaefer, Gabriele and Schmidt, Stephen and Seward, Eileen M. and Sideris, Steve and Tam, Christine and Wang, Shumei and Yeap, Siew Kuen and Yen, Ivana and Yin, Jianping and Yu, Christine and Zilberleyb, Inna and Heffron, Timothy P.},
abstractNote = {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.},
doi = {10.1021/jm501578n},
url = {https://www.osti.gov/biblio/1168859},
journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = 23,
volume = 57,
place = {United States},
year = {Mon Nov 10 00:00:00 EST 2014},
month = {Mon Nov 10 00:00:00 EST 2014}
}
Web of Science
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