Development of VER-50589 analogs as novel Hsp90 inhibitors

  • Bioorg Med Chem Lett. 2023 Jul 15;91:129375. doi: 10.1016/j.bmcl.2023.129375.
Xixi Fang  1 ,  Jinhong Feng  2 ,  Kewei Wang  3 ,  Yepeng Luan  4
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, Qingdao University Medical College, Qingdao University, Qingdao, Shandong, China; Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao University, Qingdao, Shandong, China.
  • 2. Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Ji' nan, Shandong, China.
  • 3. Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao University, Qingdao, Shandong, China.
  • 4. Department of Medicinal Chemistry, School of Pharmacy, Qingdao University Medical College, Qingdao University, Qingdao, Shandong, China. Electronic address: [email protected].
PMID: 37315698 DOI: 10.1016/j.bmcl.2023.129375
Abstract

As an important target for tumor therapy, heat shock protein 90 has attracted tremendous attention. Through structure analysis, we rationally designed three analogs of VER-50589 which is a known and potent HSP90 Inhibitor. Target inhibitory activity result showed that one compound dubbed as 12-1 exhibited strong inhibitory activity against HSP90 with an IC50 value of 9 nM. In tumor cell viability experiment, compound 12-1 robustly repressed the proliferation against six human tumor cells with IC50 values all in nanomolar range scoring over VER-50589 and geldanamycin. 12-1 was able to induce Apoptosis of tumor cells and arrest the tumor cell cycle in G0/G1 phase. Meanwhile, western blot results showed that 12-1 could significantly downregulated the expression of two HSP90 client proteins CDK4 and HER2. Finally, molecular dynamic simulation showed that compound 12-1 could fit well with ATP binding site on N-terminal of HSP90.

Keywords
Antitumor; Docking; Hsp90; Inhibitor; VER-50589.
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