Discovery of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl)acetates as potent Hsp90 inhibitors with selectivity over TRAP1 |
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| Institution: | 1. New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea;2. Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan 44919, South Korea;3. College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea;4. Western Seoul Center, Korea Basic Science Institute, Seoul 03760, South Korea;1. School of Basic Medical Sciences, Institute of Drug Discovery & Development, Zhengzhou University, Zhengzhou 450001, China;2. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China;3. Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China;4. Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001, China;1. Dep. of Chemical and Pharmaceutical Sciences, University of Ferrara, Italy;2. Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy;3. Dep. of Life Sciences, University of Modena and Reggio Emilia, Italy;4. Dep. of Molecular Medicine and Medical Biotechnology, University of Napoli Federico II, Italy;5. Dep. of Medical and Surgical Sciences, University of Foggia, Italy;1. Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore;2. School of Biological Sciences, Nanyang Technological University (NTU), Singapore 637551, Singapore;1. College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea;2. School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea;3. Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 08308, Republic of Korea;4. Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 08308, Republic of Korea;5. Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul 08308, Republic of Korea;1. Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea;2. College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea;3. Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, and College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea;4. Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Viet Nam;1. College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea;2. School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea;3. Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea;4. Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea;5. Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul 152-703, Republic of Korea |
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| Abstract: | As the most abundant heat shock protein (HSP), Hsp90 is actively involved in tumor cell growth and various responses to anti-carcinogenic stress. Hsp90 has thus emerged as a potential drug target. A structure-based drug design approach was applied to develop novel resorcinolyltriazole derivatives as Hsp90 inhibitors. Structure-activity relationships (SARs) and molecular docking were investigated to provide a rationale for binding affinity and paralog selectivity. Click chemistry between iodoethynylresorcinol and an azido derivative was used to synthesize a new family of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl) acetates that exhibited Hsp90 binding affinities of 40–100 nM (IC50). Among the synthesized molecules, the triazole alkyl acetates displayed the highest Hsp90 binding affinities. Their potency against Hsp90 was over 100-fold stronger than against TRAP1 and 1–3-fold stronger than against Grp94. In particular, compounds 18, 19, and 30 had Hsp90 inhibitory activities of ~45 nM (IC50) and they displayed over 350-fold selectivity for Hsp90 over TRAP1. |
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| Keywords: | Hsp90 TRAP1 Grp94 Inhibitor Selectivity Resorcinol Triazole |
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