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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
- Jung, Sejin; Yoon, Nam Gu; Yang, Sujae; Kim, Darong; Lee, Won Seok; Hong, Ki Bum; Lee, Changwook; Kang, Byoung Heon; Lee, Ji Hoon; Kang, Soosung
- Ewha Authors
- Issue Date
- Journal Title
- BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
- BIOORGANIC & MEDICINAL CHEMISTRY LETTERS vol. 30, no. 2
- Hsp90; TRAP1; Grp94; Inhibitor; Selectivity; Resorcinol; Triazole
- PERGAMON-ELSEVIER SCIENCE LTD
- SCI; SCIE; SCOPUS
- Document Type
- 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 similar to 45 nM (IC50) and they displayed over 350-fold selectivity for Hsp90 over TRAP1.
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