2. Academic Validation
  3. Discovery of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl)acetates as potent Hsp90 inhibitors with selectivity over TRAP1

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.
Sejin Jung 1,  Nam Gu Yoon 2,  Sujae Yang 3,  Darong Kim 1,  Won Seok Lee 1,  Ki Bum Hong 1,  Changwook Lee 2,  Byoung Heon Kang 4,  Ji Hoon Lee 5,  Soosung Kang 6
Affiliations

Affiliations

  • 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: kangbh@unist.ac.kr.
  • 5 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea. Electronic address: jhlee@dgmif.re.kr.
  • 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: sskang@ewha.ac.kr.
PMID: 31839539 DOI: 10.1016/j.bmcl.2019.126809
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.

Keywords

Grp94; Hsp90; Inhibitor; Resorcinol; Selectivity; TRAP1; Triazole.

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