title: Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors.
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.
authors.affiliation: 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.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Wurz
authors.affiliation: 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.
authors.forename: Liping H
authors.initials: LH
authors.lastname: Pettus
authors.affiliation: 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.
authors.forename: Kate
authors.initials: K
authors.lastname: Ashton
authors.affiliation: 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.
authors.forename: James
authors.initials: J
authors.lastname: Brown
authors.affiliation: 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.
authors.forename: Jian Jeffrey
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Brad
authors.initials: B
authors.lastname: Herberich
authors.affiliation: 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.
authors.forename: Fang-Tsao
authors.initials: FT
authors.lastname: Hong
authors.affiliation: 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.
authors.forename: Essa
authors.initials: E
authors.lastname: Hu-Harrington
authors.affiliation: 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.
authors.forename: Tom
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: 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.
authors.forename: David J
authors.initials: DJ
authors.lastname: St Jean
authors.affiliation: 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.
authors.forename: Seifu
authors.initials: S
authors.lastname: Tadesse
authors.affiliation: Medicinal Chemistry, Chemical Process R&D, Analytical R&D, Amgen Inc. , 360 Binney Avenue, Cambridge, Massachusetts 02142-1011, United States.
authors.forename: David
authors.initials: D
authors.lastname: Bauer
authors.affiliation: Medicinal Chemistry, Chemical Process R&D, Analytical R&D, Amgen Inc. , 360 Binney Avenue, Cambridge, Massachusetts 02142-1011, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: Kubryk
authors.affiliation: 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.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhan
authors.affiliation: 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.
authors.forename: Keegan
authors.initials: K
authors.lastname: Cooke
authors.affiliation: 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.
authors.forename: Petia
authors.initials: P
authors.lastname: Mitchell
authors.affiliation: 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.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Andrews
authors.affiliation: 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.
authors.forename: Faye
authors.initials: F
authors.lastname: Hsieh
authors.affiliation: 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.
authors.forename: Dean
authors.initials: D
authors.lastname: Hickman
authors.affiliation: 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.
authors.forename: Nataraj
authors.initials: N
authors.lastname: Kalyanaraman
authors.affiliation: 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.
authors.forename: Tian
authors.initials: T
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Darren L
authors.initials: DL
authors.lastname: Reid
authors.affiliation: 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.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Lobenhofer
authors.affiliation: 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.
authors.forename: Dina A
authors.initials: DA
authors.lastname: Andrews
authors.affiliation: 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.
authors.forename: Nancy
authors.initials: N
authors.lastname: Everds
authors.affiliation: 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.
authors.forename: Roberto
authors.initials: R
authors.lastname: Guzman
authors.affiliation: Medicinal Chemistry, Chemical Process R&D, Analytical R&D, Amgen Inc. , 360 Binney Avenue, Cambridge, Massachusetts 02142-1011, United States.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Parsons
authors.affiliation: 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.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Hedley
authors.affiliation: 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.
authors.forename: Jason
authors.initials: J
authors.lastname: Tedrow
authors.affiliation: 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.
authors.forename: Oliver R
authors.initials: OR
authors.lastname: Thiel
authors.affiliation: Medicinal Chemistry, Chemical Process R&D, Analytical R&D, Amgen Inc. , 360 Binney Avenue, Cambridge, Massachusetts 02142-1011, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Potter
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Radinsky
authors.affiliation: 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.
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Beltran
authors.affiliation: 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.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Tasker
keywords: EGFR; EGFR T790M mutant; Epidermal growth factor receptor; irreversible inhibitor; kinase inhibitor; nonsmall cell lung cancer