Beljkas Milan, Ruzic Dusan, Djuric Ana, Vuletic Ana, Tchiehe Guilaine Nchugoua, Jallet Corinne, Cadet-Daniel Véronique, Arimondo Paola B, Santibanez Juan F, Srdic-Rajic Tatjana, Nikolic Katarina, Oljacic Slavica, Petkovic Milos
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia.
Future Med Chem. 2025 Feb;17(4):393-407. doi: 10.1080/17568919.2025.2459589. Epub 2025 Jan 30.
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 HDAC/ROCK multitarget inhibitors in pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC).
A molecular docking study performed with the Gold software was used to develop HDAC/ROCK multitarget inhibitors. IC 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).
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 IC values of 5.81 μM, 3.87 μM and 19.57 μM. In addition, it demonstrated great anti-invasive and anti-migratory effects.
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.
为了同时调节表观遗传系统和蛋白激酶途径，我们选择组蛋白去乙酰化酶（HDAC）和Rho相关蛋白激酶（ROCK）作为目标，以开发具有额外抗转移特性的潜在多靶点抗癌药物。我们在此报告胰腺导管腺癌（PDAC）和三阴性乳腺癌（TNBC）中HDAC/ROCK多靶点抑制剂的合理设计、合成及生物学评价。
使用Gold软件进行分子对接研究，以开发HDAC/ROCK多靶点抑制剂。通过酶测定法确定IC值。使用三阴性乳腺癌细胞（MDA-MB-231和HCC 1973）和胰腺导管腺癌细胞（Panc-1和MiaPaCa-2）评估抑制剂的细胞毒性、抗迁移和抗侵袭特性。
显示对HDAC6、ROCK1和ROCK2有显著抑制作用。同时，该化合物对MDA-MB-231、MiaPaCa-2和Panc-1细胞系表现出强烈的抗增殖作用，IC值分别为5.81 μM、3.87 μM和19.57 μM。此外，它还表现出很强的抗侵袭和抗迁移作用。
本研究结果强烈表明，同时抑制ROCK和HDACs作为一种有前景的治疗策略在癌症治疗进展中具有巨大潜力。
