Identification of a new series of potent diphenol HSP90 inhibitors by fragment merging and structure-based optimization |
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| Institution: | 1. 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;2. Shanghai Institute of Applied Physics, Chinese Academy of Sciences, 239 Zhangheng Road, Shanghai 201204, China;3. Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;4. 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;1. Departamento de Síntese de Fármacos, Instituto de Tecnologia em Fármacos, Farmanguinhos-FIOCRUZ, Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil;2. Programa de Pós Graduação em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil;3. Centro de Pesquisas René Rachou, CPqRR-FIOCRUZ, Belo Horizonte, MG 30190-002, Brazil;4. Programa de Pós Graduação em Medicina Molecular, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil;5. Laboratório de Cristalografia de Proteínas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café s/n Monte Alegre, 14040-903 Ribeirão Preto, SP, Brazil;6. Grupo de Biofísica Computacional e Modelagem Molecular, Programa de Computação Científica (PROCC), FIOCRUZ, Av. Brasil 4365, Rio de Janeiro, CEP 21040-360, Brazil;1. College of Chemistry, Chemical Engineering and Environmental Engineering, Liaoning Shihua University, Dandong Lu West 1, Fushun 113001, PR China;2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China;3. The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, PR China;4. School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;5. Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Lu, Shenyang 110016, PR China;6. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China;1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China;2. The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, PR China;3. Shanghai Institute of Applied Physics, Chinese Academy of Sciences, 239 Zhang Heng Road, Pudong New District, Shanghai 201203, PR China;1. Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States;2. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, United States;3. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, United States;1. School of Chemical Sciences, University of Auckland, Auckland, New Zealand;2. Department of Pharmacology & Clinical Pharmacology, University of Auckland, Auckland, New Zealand;3. Maurice Wilkins Centre for Molecular Biodiscovery, New Zealand;1. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, People’s Republic of China;2. Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, People’s Republic of China;3. Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium |
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| 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. |
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| Keywords: | Heat shock protein HSP90 Fragment-based drug discovery Anticancer |
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