2. Academic Validation
  3. New Class of Hsp90 C-Terminal Domain Inhibitors with Anti-tumor Properties against Triple-Negative Breast Cancer

New Class of Hsp90 C-Terminal Domain Inhibitors with Anti-tumor Properties against Triple-Negative Breast Cancer

  • J Med Chem. 2024 Aug 8;67(15):12984-13018. doi: 10.1021/acs.jmedchem.4c00932.
Živa Zajec 1,  Jaka Dernovšek 1,  Jernej Cingl 1,  Iza Ogris 2,  Marius Gedgaudas 3,  Asta Zubrienė 3,  Ana Mitrović 1 4,  Simona Golič Grdadolnik 2,  Martina Gobec 1,  Tihomir Tomašič 1
Affiliations

Affiliations

  • 1 Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
  • 2 Laboratory for Molecular Structural Dynamics, Theory Department, National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia.
  • 3 Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, Lithuania.
  • 4 Department of Biotechnology, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia.
PMID: 39042910 DOI: 10.1021/acs.jmedchem.4c00932
Abstract

Triple-negative breast Cancer (TNBC) remains a treatment challenge and requires innovative therapies. HSP90, crucial for the stability of numerous oncogenic proteins, has emerged as a promising therapeutic target. In this study, we present the optimization of the HSP90 C-terminal domain (CTD) inhibitor TVS21. Biochemical methods, NMR binding studies, and molecular modeling were employed to investigate the binding of representative analogs to HSP90. The newly synthesized analogs showed increased antiproliferative activity in breast Cancer cell lines, including the MDA-MB-231 TNBC cell line. Compounds 89 and 104 proved to be the most effective, inducing Apoptosis, slowing proliferation, and degrading key oncogenic proteins without inducing a heat shock response. In vivo, compound 89 showed comparable efficacy to the clinical candidate AUY922 and a better safety profile in a TNBC xenograft model. These results highlight the promise of HSP90 CTD inhibitors for TNBC therapy, potentially filling a significant treatment gap.

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