title: Discovery of benzofuran-3(2H)-one derivatives as novel DRAK2 inhibitors that protect islet β-cells from apoptosis.
abstract: Death-associated protein kinase-related apoptosis-inducing kinase-2 (DRAK2) is a serine/threonine kinase that plays a key role in a wide variety of cell death signaling pathways. Inhibition of DRAK2 was found to efficiently protect islet β-cells from apoptosis and hence DRAK2 inhibitors represent a promising therapeutic strategy for the treatment of diabetes. Only very few chemical entities targeting DRAK2 are currently known. We carried out a high throughput screening and identified compound 4 as a moderate DRAK2 inhibitor with an IC50value of 3.15 μM. Subsequent SAR studies of hit compound 4 led to the development of novel benzofuran-3(2H)-one series of DRAK2 inhibitors with improved potency and favorable selectivity profiles against 26 selected kinases. Importantly, most potent compounds 40 (IC50= 0.33 μM) and 41 (IC50= 0.25 μM) were found to protect islet β-cells from apoptosis in dose-dependent manners. These data support the notion that small molecule inhibitors of DRAK2 represents a promising strategy for the treatment of diabetes.
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Lu
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
authors.forename: Yu-Fei
authors.initials: YF
authors.lastname: Liu
authors.affiliation: Laboratory of Immunology and Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, 900 rue St-Denis, Montréal, Québec, Canada.
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China; Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory of Immunology and Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, 900 rue St-Denis, Montréal, Québec, Canada. Electronic address: jianping.wu@umontreal.ca.
authors.forename: Jiangping
authors.initials: J
authors.lastname: Wu
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China. Electronic address: jyli@simm.ac.cn.
authors.forename: Jing-Ya
authors.initials: JY
authors.lastname: Li
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China. Electronic address: lfyu@sat.ecnu.edu.cn.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Yu
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China. Electronic address: fyang@chem.ecnu.edu.cn.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors*; D001402:B-Lymphocytes / Q000166:cytology*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000188:drug therapy; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D007515:Islets of Langerhans / Q000166:cytology*; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D051017:Apoptosis Regulatory Proteins; D001572:Benzofurans; D020011:Protective Agents; D017346:Protein Serine-Threonine Kinases; C115489:STK17B protein, human
keywords: Apoptosis; DRAK2 inhibitor; Diabetes; Islet β-cell protection