title: Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib.
abstract: Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).
authors.affiliation: La Jolla Laboratories, Pfizer Worldwide Research and Development , 10770 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Qinhua
authors.initials: Q
authors.lastname: Huang
authors.forename: Ted W
authors.initials: TW
authors.lastname: Johnson
authors.forename: Simon
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authors.lastname: Bailey
authors.forename: Alexei
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authors.lastname: Brooun
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Bunker
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Burke
authors.forename: Michael R
authors.initials: MR
authors.lastname: Collins
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Cook
authors.forename: J Jean
authors.initials: JJ
authors.lastname: Cui
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Dack
authors.forename: Judith G
authors.initials: JG
authors.lastname: Deal
authors.forename: Ya-Li
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authors.lastname: Deng
authors.forename: Dac
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authors.lastname: Dinh
authors.forename: Lars D
authors.initials: LD
authors.lastname: Engstrom
authors.forename: Mingying
authors.initials: M
authors.lastname: He
authors.forename: Jacqui
authors.initials: J
authors.lastname: Hoffman
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hoffman
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Johnson
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kania
authors.forename: Hieu
authors.initials: H
authors.lastname: Lam
authors.forename: Justine L
authors.initials: JL
authors.lastname: Lam
authors.forename: Phuong T
authors.initials: PT
authors.lastname: Le
authors.forename: Qiuhua
authors.initials: Q
authors.lastname: Li
authors.forename: Laura
authors.initials: L
authors.lastname: Lingardo
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Melissa West
authors.initials: MW
authors.lastname: Lu
authors.forename: Michele
authors.initials: M
authors.lastname: McTigue
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Palmer
authors.forename: Paul F
authors.initials: PF
authors.lastname: Richardson
authors.forename: Neal W
authors.initials: NW
authors.lastname: Sach
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: Tod
authors.initials: T
authors.lastname: Smeal
authors.forename: Graham L
authors.initials: GL
authors.lastname: Smith
authors.forename: Albert E
authors.initials: AE
authors.lastname: Stewart
authors.forename: Sergei
authors.initials: S
authors.lastname: Timofeevski
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Tsaparikos
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Huichun
authors.initials: H
authors.lastname: Zhu
authors.forename: Jinjiang
authors.initials: J
authors.lastname: Zhu
authors.forename: Helen Y
authors.initials: HY
authors.lastname: Zou
authors.forename: Martin P
authors.initials: MP
authors.lastname: Edwards
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases