title: Identification of a new series of potent diphenol HSP90 inhibitors by fragment merging and structure-based optimization.
abstract: Heat shock protein 90 (HSP90) is a molecular chaperone to fold and maintain the proper conformation of many signaling proteins, especially some oncogenic proteins and mutated unstable proteins. Inhibition of HSP90 was recognized as an effective approach to simultaneously suppress several aberrant signaling pathways, and therefore it was considered as a novel target for cancer therapy. Here, by integrating several techniques including the fragment-based drug discovery method, fragment merging, computer aided inhibitor optimization, and structure-based drug design, we were able to identify a series of HSP90 inhibitors. Among them, inhibitors 13, 32, 36 and 40 can inhibit HSP90 with IC50 about 20-40 nM, which is at least 200-fold more potent than initial fragments in the protein binding assay. These new HSP90 inhibitors not only explore interactions with an under-studied subpocket, also offer new chemotypes for the development of novel HSP90 inhibitors as anticancer drugs.
authors.affiliation: Department of Medicinal Chemistry, National Key Laboratory of New Drug, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ren
authors.affiliation: Shanghai Institute of Applied Physics, Chinese Academy of Sciences, 239 Zhangheng Road, Shanghai 201204, China; CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Yueqin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Wuyan
authors.initials: W
authors.lastname: Chen
authors.affiliation: Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Aijun
authors.initials: A
authors.lastname: Shen
authors.affiliation: Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Hongchun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, National Key Laboratory of New Drug, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Danqi
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, National Key Laboratory of New Drug, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Danyan
authors.initials: D
authors.lastname: Cao
authors.affiliation: Department of Medicinal Chemistry, National Key Laboratory of New Drug, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Yanlian
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, National Key Laboratory of New Drug, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Naixia
authors.initials: N
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: mygeng@simm.ac.cn.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.affiliation: Shanghai Institute of Applied Physics, Chinese Academy of Sciences, 239 Zhangheng Road, Shanghai 201204, China. Electronic address: hejh@sinap.ac.cn.
authors.forename: Jianhua
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Medicinal Chemistry, National Key Laboratory of New Drug, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: bxiong@simm.ac.cn.
authors.forename: Bing
authors.initials: B
authors.lastname: Xiong
authors.affiliation: Department of Medicinal Chemistry, National Key Laboratory of New Drug, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D007527:Isoenzymes; D010636:Phenols; D003577:Cytochrome P-450 Enzyme System
keywords: Anticancer; Fragment-based drug discovery; HSP90; Heat shock protein