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Lee, Changwook
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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

Author(s)
Jung, SejinYoon, Nam GuYang, SujaeKim, DarongLee, Won SeokHong, Ki BumLee, ChangwookKang, Byoung HeonLee, Ji HoonKang, Soosung
Issued Date
2020-01
DOI
10.1016/j.bmcl.2019.126809
URI
https://scholarworks.unist.ac.kr/handle/201301/30946
Fulltext
https://www.sciencedirect.com/science/article/pii/S0960894X19307784?via%3Dihub
Citation
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, v.30, no.2, pp.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 similar to 45 nM (IC50) and they displayed over 350-fold selectivity for Hsp90 over TRAP1.
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
ISSN
0960-894X
Keyword (Author)
Hsp90TRAP1Grp94InhibitorSelectivityResorcinolTriazole
Keyword
MOLECULAR CHAPERONECRYSTAL-STRUCTUREPROTEINSPECIFICITYHSP90-ALPHA/BETAIDENTIFICATIONGANETESPIBAFFINITYCOMPLEX

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