Discovery of novel heat shock protein (Hsp90) inhibitors based on luminespib with potent antitumor activity

[Display omitted] A series of isosteric surrogates of the 4-phenyl group in luminespib were investigated as new scaffolds of the Hsp90 inhibitor for the discovery of novel antitumor agents. Among the synthesized surrogates of isoxazole and pyrazole, compounds 4a, 5e and 12b exhibited potent Hsp90 in...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2020-06, Vol.30 (12), p.127165-127165, Article 127165
Main Authors: Jung, Juyoung, Kwon, Jinsun, Hong, Soojung, Moon, An-Na, Jeong, Jinah, Kwon, Sungwook, Kim, Jeong-ah, Lee, Myoungjae, Lee, Hongsub, Lee, Jin Hee, Lee, Jeewoo
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antitumor agent
Cell Line, Tumor
Cell Proliferation - drug effects
Dose-Response Relationship, Drug
Drug Discovery
Drug Screening Assays, Antitumor
Heat shock protein 90
HSP90 Heat-Shock Proteins - antagonists & inhibitors
HSP90 Heat-Shock Proteins - metabolism
Humans
Isoxazoles - chemical synthesis
Isoxazoles - chemistry
Isoxazoles - pharmacology
Luminespib
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Neoplasms, Experimental - drug therapy
Neoplasms, Experimental - metabolism
Neoplasms, Experimental - pathology
Resorcinols - chemical synthesis
Resorcinols - chemistry
Resorcinols - pharmacology
Structure-Activity Relationship
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Summary:[Display omitted] A series of isosteric surrogates of the 4-phenyl group in luminespib were investigated as new scaffolds of the Hsp90 inhibitor for the discovery of novel antitumor agents. Among the synthesized surrogates of isoxazole and pyrazole, compounds 4a, 5e and 12b exhibited potent Hsp90 inhibition in ATPase activity and Her2 degradation assays and significant antitumor activity in A2780 and HCT116 cell lines. Animal studies indicated that compared to luminespib, their activities were superior in A2780 or NCI-H1975 tumor xenograft models. A molecular modeling study demonstrated that compound 4a could fit nicely into the N-terminal ATP binding pocket.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2020.127165