2. Academic Validation
  3. Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors

Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors

  • ACS Med Chem Lett. 2015 Jul 27;6(9):987-92. doi: 10.1021/acsmedchemlett.5b00193.
Ryan P Wurz 1,  Liping H Pettus 1,  Kate Ashton 1,  James Brown 1,  Jian Jeffrey Chen 1,  Brad Herberich 1,  Fang-Tsao Hong 1,  Essa Hu-Harrington 1,  Tom Nguyen 1,  David J St Jean Jr 1,  Seifu Tadesse 1,  David Bauer 2,  Michele Kubryk 2,  Jinghui Zhan 1,  Keegan Cooke 1,  Petia Mitchell 1,  Kristin L Andrews 1,  Faye Hsieh 1,  Dean Hickman 1,  Nataraj Kalyanaraman 1,  Tian Wu 1,  Darren L Reid 1,  Edward K Lobenhofer 1,  Dina A Andrews 1,  Nancy Everds 1,  Roberto Guzman 1,  Andrew T Parsons 2,  Simon J Hedley 1,  Jason Tedrow 1,  Oliver R Thiel 1,  Matthew Potter 2,  Robert Radinsky 1,  Pedro J Beltran 1,  Andrew S Tasker 1
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Oncology Research, Molecular Structure, Pharmacokinetics and Drug Metabolism, Oral Delivery - Product and Process Development, Discovery Toxicology, Pathology, Chemical Process R&D, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
  • 2 Medicinal Chemistry, Chemical Process R&D, Analytical R&D, Amgen Inc. , 360 Binney Avenue, Cambridge, Massachusetts 02142-1011, United States.
PMID: 26396685 DOI: 10.1021/acsmedchemlett.5b00193
Abstract

In nonsmall cell lung Cancer (NSCLC), the threonine(790)-methionine(790) (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido[2,3-d]pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound 24 which potently inhibits gefitinib-resistant EGFR(L858R,T790M) with 100-fold selectivity over wild-type EGFR. Compound 24 displays strong antiproliferative activity against the H1975 nonsmall cell lung Cancer cell line, the first line mutant HCC827 cell line, and promising antitumor activity in an EGFR(L858R,T790M) driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR.

Keywords

EGFR; EGFR T790M mutant; Epidermal growth factor receptor; irreversible inhibitor; kinase inhibitor; nonsmall cell lung cancer.

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