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Title: 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:
 [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
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}
}

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Works referenced in this record:

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Epidermal growth factor receptor mutations in lung cancer
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EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib
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Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib
journal, May 2005


Setting expectations in molecular optimizations: Strengths and limitations of commonly used composite parameters
journal, November 2013


Covalent Modifiers: An Orthogonal Approach to Drug Design
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Metabolic Stability Screen for Drug Discovery Using Cassette Analysis and Column Switching
journal, January 2007


Drug−Protein Adducts:  An Industry Perspective on Minimizing the Potential for Drug Bioactivation in Drug Discovery and Development
journal, January 2004


Structure-Based Design of Orally Bioavailable 1 H -Pyrrolo[3,2- c ]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)
journal, December 2013


EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib
journal, August 2004


AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer
journal, June 2014


Drug discovery for a new generation of covalent drugs
journal, May 2012


Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer
journal, September 2009


Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer
journal, October 2010


The role of ligand efficiency metrics in drug discovery
journal, January 2014


Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor–resistant non-small cell lung cancer (NSCLC).
journal, May 2014


Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M
journal, December 2012


A Medicinal Chemist’s Guide to Molecular Interactions
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First-in-human evaluation of CO-1686, an irreversible, selective, and potent tyrosine kinase inhibitor of EGFR T790M.
journal, May 2013


Setting expectations in molecular optimizations: Strengths and limitations of commonly used composite parameters
journal, November 2013


Lead identification of novel and selective TYK2 inhibitors
journal, September 2013


Resistance in the land of molecular cancer therapeutics
journal, August 2002


A Medicinal Chemist’s Guide to Molecular Interactions
journal, July 2010


Structure-Based Design of Orally Bioavailable 1 H -Pyrrolo[3,2- c ]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)
journal, December 2013


Drug−Protein Adducts:  An Industry Perspective on Minimizing the Potential for Drug Bioactivation in Drug Discovery and Development
journal, January 2004


Epidermal growth factor receptor mutations in lung cancer
journal, March 2007


Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer
journal, October 2010


Flying under the radar: the new wave of BCR–ABL inhibitors
journal, October 2007


Targeting Targeted Therapy
journal, May 2004


EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib
journal, August 2004


Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib
journal, May 2005


The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
journal, January 2008


Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor
journal, August 2002


EGFR Mutations in Non-Small Cell Lung Carcinomas May Predict Response to Gefitinib
journal, March 2005


Oncogene addiction: setting the stage for molecularly targeted cancer therapy
journal, December 2007


Gefitinib Induces Apoptosis in the EGFR L858R Non–Small-Cell Lung Cancer Cell Line H3255
journal, October 2004


The Epidermal Growth Factor Receptor D761Y Mutation and Effect of Tyrosine Kinase Inhibitor
journal, June 2007


Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR -Mutant Lung Cancers
journal, March 2013


The EGFR T790M Mutation in Acquired Resistance to an Irreversible Second-Generation EGFR Inhibitor
journal, January 2012


In Vitro and In Vivo Characterization of Irreversible Mutant-Selective EGFR Inhibitors That Are Wild-Type Sparing
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Maximizing the Benefits of Off-Target Kinase Inhibitor Activity
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Inhibition of EGFR Signaling: All Mutations Are Not Created Equal
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Drug discovery for a new generation of covalent drugs
journal, May 2012


Metabolic Stability Screen for Drug Discovery Using Cassette Analysis and Column Switching
journal, January 2007


Works referencing / citing this record:

Unraveling structural requirements of amino-pyrimidine T790M/L858R double mutant EGFR inhibitors: 2D and 3D QSAR study
journal, July 2018


Gossypol Inhibits Non-small Cell Lung Cancer Cells Proliferation by Targeting EGFRL858R/T790M
journal, July 2018


Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions
journal, September 2016


Acetylation of C/EBPα inhibits its granulopoietic function
journal, March 2016