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
  • 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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