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

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.
Juyoung Jung 1,  Jinsun Kwon 2,  Soojung Hong 3,  An-Na Moon 3,  Jinah Jeong 3,  Sungwook Kwon 3,  Jeong-Ah Kim 3,  Myoungjae Lee 3,  Hongsub Lee 3,  Jin Hee Lee 3,  Jeewoo Lee 4
Affiliations

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: [email protected].
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.

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