title: Design, Synthesis, and Structure-Activity Relationship Studies of 3-(Phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Derivatives as a New Class of Src Inhibitors with Potent Activities in Models of Triple Negative Breast Cancer.
abstract: A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were designed and synthesized. Structure-activity relationship (SAR) analysis of these compounds led to the discovery of compound 1j, which showed the highest inhibitory potency against the Src kinase and the most potent antiviability activity against the typical TNBC cell line MDA-MB-231 among all the synthesized compounds. Further kinase inhibition assays showed that compound 1j was a multikinase inhibitor and potently inhibited Src (IC50 = 0.0009 μM) and MAPK signaling protein kinases B-RAF and C-RAF. In an MDA-MB-231 xenograft mouse model, a once-daily dose of compound 1j at 30 mg/kg for 18 days completely suppressed the tumor growth with a tumor inhibition rate larger than 100% without obvious toxicity. It also displayed good pharmacokinetic properties in a preliminary pharmacokinetic assay. Western blot and immunohistochemical assays revealed that compound 1j significantly inhibited Src and MAPK signaling and markedly induced apoptosis in tumor tissues.
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Zhang
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Ming-Wu
authors.initials: MW
authors.lastname: Zheng
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Li
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Xing-Dong
authors.initials: XD
authors.lastname: Lin
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Huang
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhong
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Guo-Bo
authors.initials: GB
authors.lastname: Li
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Rong-Jie
authors.initials: RJ
authors.lastname: Zhang
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Wan-Ting
authors.initials: WT
authors.lastname: Lin
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Xiao-Ai
authors.initials: XA
authors.lastname: Wu
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Yang
authors.affiliation: ‡Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin 300071, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Chen
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Ying-Lan
authors.initials: YL
authors.lastname: Zhao
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
authors.affiliation: †State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D000114:Acetylene / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D064593:Heterografts; D006801:Humans; D008297:Male; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: C000599957:3-((4-amino-1-ethyl-1H-pyrazolo(3,4-d)pyrimidin-3-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D011720:Pyrazoles; D011743:Pyrimidines; D019061:src-Family Kinases; D000114:Acetylene