title: Discovery and characterization of novel imidazopyridine derivative CHEQ-2 as a potent CDC25 inhibitor and promising anticancer drug candidate.
abstract: Cell division cycle (CDC) 25 proteins are key phosphatases regulating cell cycle transition and proliferation via the interactions with CDK/Cyclin complexes. Overexpression of CDC25 proteins is frequently observed in cancer and is related to aggressiveness, high-grade tumors and poor prognosis. Thus, inhibiting CDC25 activity in cancer treatment appears a good therapeutic strategy. In this article, refinement of the initial hit XDW-1 by synthesis and screening of a focused compound library led to the identification of a novel set of imidazopyridine derivatives as potent CDC25 inhibitors. Among them, the most potent molecule was CHEQ-2, which could efficiently inhibit the activities of CDC25A/B enzymes as well as the proliferation of various different types of cancer cell lines in vitro assay. Moreover, CHEQ-2 triggered S-phase cell cycle arrest in MCF-7, HepG2 and HT-29 cell lines, accompanied by generation of ROS, mitochondrial dysfunction and apoptosis. Besides, oral administration of CHEQ-2 (10 mg/kg) significantly inhibited xenografted human liver tumor growth in nude mice, while demonstrated extremely low toxicity (LD50 > 2000 mg/kg). These findings make CHEQ-2 a good starting point for further investigation and structure modification.
authors.affiliation: Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
authors.forename: Yu'ning
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Kang
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: zhanpeng1982@163.com.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhan
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: xinyongllab@163.com.
authors.forename: Xinyong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: zhangqzh@sdu.edu.cn.
authors.forename: Qingzhu
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008968:Molecular Conformation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011724:Pyridazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C000595838:1-(3,4-dihydroxyphenyl)-2-((1-mesityl-1H-imidazo(4,5-c)pyridin-2-yl)thio)ethanone; D000970:Antineoplastic Agents; D007093:Imidazoles; D011724:Pyridazines; D011725:Pyridines; D020687:cdc25 Phosphatases
keywords: Anticancer agents; Apoptosis; CDC25 inhibitor; Cell cycle arrest; Reactive oxygen species