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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

Title
Discovery of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl)acetates as potent Hsp90 inhibitors with selectivity over TRAP1
Authors
Jung, SejinYoon, Nam GuYang, SujaeKim, DarongLee, Won SeokHong, Ki BumLee, ChangwookKang, Byoung HeonLee, Ji HoonKang, Soosung
Ewha Authors
강수성
Issue Date
2020
Journal Title
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
ISSN
0960-894XJCR Link

1464-3405JCR Link
Citation
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS vol. 30, no. 2
Keywords
Hsp90TRAP1Grp94InhibitorSelectivityResorcinolTriazole
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Indexed
SCI; SCIE; SCOPUS WOS scopus
Document Type
Article
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 similar to 45 nM (IC50) and they displayed over 350-fold selectivity for Hsp90 over TRAP1.
DOI
10.1016/j.bmcl.2019.126809
Appears in Collections:
약학대학 > 약학과 > Journal papers
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