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

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

doi:10.1016/j.bmcl.2020.127165

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

Bioorg Med Chem Lett. 2020 Jun 15;30(12):127165. doi: 10.1016/j.bmcl.2020.127165. Epub 2020 Apr 2.

Authors

Affiliations

¹ Research Laboratories, Ildong Pharmaceutical Co., Hwaseong-si, Gyeonggi-do 18449, South Korea; Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
² AIMS BioScience Co., 2, Baumoe-ro 27-gil, Seocho-gu, Seoul 06752, South Korea.
³ Research Laboratories, Ildong Pharmaceutical Co., Hwaseong-si, Gyeonggi-do 18449, South Korea.
⁴ Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, South Korea. Electronic address: jeewoo@snu.ac.kr.

PMID: 32305165
DOI: 10.1016/j.bmcl.2020.127165

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.

Keywords: Antitumor agent; Heat shock protein 90; Luminespib.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / metabolism
Humans
Isoxazoles / chemical synthesis
Isoxazoles / chemistry
Isoxazoles / pharmacology*
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

Substances

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