2. Academic Validation
  3. Pioneering first-in-class HDAC-ROCK inhibitors as potential multitarget anticancer agents

Pioneering first-in-class HDAC-ROCK inhibitors as potential multitarget anticancer agents

  • Future Med Chem. 2025 Feb;17(4):393-407. doi: 10.1080/17568919.2025.2459589.
Milan Beljkas 1,  Dusan Ruzic 1,  Ana Djuric 2,  Ana Vuletic 2,  Guilaine Nchugoua Tchiehe 3,  Corinne Jallet 3,  Véronique Cadet-Daniel 3,  Paola B Arimondo 3,  Juan F Santibanez 4,  Tatjana Srdic-Rajic 2,  Katarina Nikolic 1,  Slavica Oljacic 1,  Milos Petkovic 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
  • 2 Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia.
  • 3 Department of Structural Biology and Chemistry, Epigenetic Chemical Biology, Institut Pasteur, Université Paris Cité, CNRS UMR3523 Chem4Life, Department of Structural Biology and Chemistry, Paris, France.
  • 4 Group for Molecular Oncology, Institute for Medical Research, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.
  • 5 Department of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
PMID: 39885716 DOI: 10.1080/17568919.2025.2459589
Abstract

Aim: With the aim of simultaneously modulating the epigenetic system and the protein kinase pathway, we selected the Enzyme histone deacetylase (HDAC) and the Rho-associated protein kinases (ROCK) as desired targets to develop potential multitarget Anticancer agents with additional antimetastatic properties. We report here the rational design, synthesis, and biological evaluation of the first-in-class HDAC/ROCK multitarget inhibitors in pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast Cancer (TNBC).

Materials and methods: A molecular docking study performed with the Gold software was used to develop HDAC/ROCK multitarget inhibitors. IC50 values were determined by Enzyme assays. The cytotoxicity, anti-migratory and anti-invasive properties of the inhibitors were evaluated using triple-negative breast Cancer cells (MDA-MB-231 and HCC 1973) and pancreatic ductal adenocarcinoma cells (Panc-1 and MiaPaCa-2).

Results: C-9 showed significant inhibition of HDAC6, ROCK1 and ROCK2. At the same time, this compound showed strong antiproliferative effects on MDA-MB-231, MiaPaCa-2 and Panc-1 cell lines with IC50 values of 5.81 μM, 3.87 μM and 19.57 μM. In addition, it demonstrated great anti-invasive and anti-migratory effects.

Conclusion: The findings of this study strongly suggest that the simultaneous inhibition of ROCK and HDACs holds significant potential as a promising therapeutic strategy in the advancement of Cancer treatment.

Keywords

Histone deacetylase; Rho-associated protein kinases; breast cancer; multitarget‐directed ligands; pancreatic ductal adenocarcinoma.

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