title: Design, synthesis and pharmacological evaluation of 2-(thiazol-2-amino)-4-arylaminopyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors.
abstract: A series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) was developed by incorporation of a substituted 2-aminothiazole component as the C-2 substituent of the center pyrimidine core. Compound 5i showed highest potency of 12.4 nM against ALK and 24.1 nM against ALK gatekeeper mutation L1196M. Although only having moderate cellular potency in the SUP-M2 cells harboring NPM-ALK, compound 5i showed good kinase selectivity and dose-dependently inhibited phosphorylation of ALK and its down-stream signaling pathways.
authors.affiliation: CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China.
authors.forename: Xihua
authors.initials: X
authors.lastname: Yue
authors.affiliation: CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China.
authors.forename: Zilan
authors.initials: Z
authors.lastname: Song
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Peng
authors.affiliation: CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Guo
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China.
authors.forename: Yinchun
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Molecular Imaging Program at Stanford, Bio-X Program, Department of Radiology, School of Medicine, Stanford University, Stanford, CA 94305-5484, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China. Electronic address: mygeng@simm.ac.cn.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.affiliation: CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Shanghai 201203, China. Electronic address: aozhang@simm.ac.cn.
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: 2,4-Diarylaminopyrimidine; 2-Aminothiazole; ALK kinase; Gatekeeper mutation; Non-small-cell lung cancer