title: Discovery of 2-arylamino-4-(1-methyl-3-isopropylsulfonyl-4-pyrazol-amino)pyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors.
abstract: A new series of 2,4-diamino pyrimidine derivatives with a sulfone-substituted pyrazole right side-chain were discovered as potent anaplastic lymphoma kinase inhibitors. Structure-activity relationship of the left side-chain on phenyl substitutions were explored which delivered many potent ALK inhibitors. Among them, 29a showed favorable pharmacokinetic profiles in rats and dogs together with significant antitumor efficacy in EML4-ALK fusion xenograft model.
authors.affiliation: Department of Applied Chemistry, Beijing Institute of Technology, Zhongguancun South Street, Beijing 100081, China; Beijing Pearl Biotech Ltd, No. 203, Section 2, Wangjing Lize Zhongyuan, Chaoyang District, Beijing 100102, China.
authors.forename: Peilong
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China. Electronic address: dongjiaqiang@crownbio.com.
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Dong
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Boyu
authors.initials: B
authors.lastname: Zhong
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Deyi
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Can
authors.initials: C
authors.lastname: Jin
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Xuejing
authors.initials: X
authors.lastname: Meng
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Desheng
authors.initials: D
authors.lastname: Sun
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Xiangyuan
authors.initials: X
authors.lastname: Xu
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Ji
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Li
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Guowei
authors.initials: G
authors.lastname: Song
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Joe
authors.initials: J
authors.lastname: Shih
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Ruihao
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Guojun
authors.initials: G
authors.lastname: Hou
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D060326:Chemistry Techniques, Synthetic; D004285:Dogs; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; Antitumor efficacy; Kinase inhibitor; NSCLC; PK properties