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

Abstract

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.

• Authors: Juyoung Jung, Jinsun Kwon, Soojung Hong, An-Na Moon, Jinah Jeong, Sungwook Kwon, Jeong-Ah Kim, Myoungjae Lee, Hongsub Lee, Jin Hee Lee, Jeewoo Lee
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 30 Issue 12 Pg. 127165 (06 15 2020) ISSN: 1464-3405 [Electronic] England
• PMID: 32305165 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• Isoxazoles
• Resorcinols

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Discovery
• Drug Screening Assays, Antitumor
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Isoxazoles (chemical synthesis, chemistry, pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Structure
• Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Resorcinols (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship