Discovery of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl)acetates as potent Hsp90 inhibitors with selectivity over TRAP1
- Bioorg Med Chem Lett. 2020 Jan 15;30(2):126809. doi: 10.1016/j.bmcl.2019.126809.
- 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. Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan 44919, South Korea. Electronic address: [email protected].
- 5. New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea. Electronic address: [email protected].
- 6. College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea; Western Seoul Center, Korea Basic Science Institute, Seoul 03760, South Korea. Electronic address: [email protected].
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.