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

Area of Science:

• Oncology
• Medicinal Chemistry
• Epigenetics

Background:

• Pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC) are aggressive cancers with limited treatment options.
• Simultaneous targeting of epigenetic regulators (HDACs) and protein kinases (ROCK) offers a promising strategy for novel anticancer agents.
• Developing multitarget inhibitors with antimetastatic properties is crucial for improving patient outcomes.

Purpose of the Study:

• To rationally design, synthesize, and evaluate the first-in-class HDAC/ROCK multitarget inhibitors.
• To assess the potential of these inhibitors in treating PDAC and TNBC.
• To investigate the antimetastatic capabilities of the developed compounds.

Main Methods:

• Molecular docking studies using Gold software to guide inhibitor design.
• Enzyme assays to determine IC50 values for HDAC and ROCK inhibition.
• In vitro evaluation of cytotoxicity, anti-migratory, and anti-invasive properties in relevant cancer cell lines (MDA-MB-231, HCC 1973, Panc-1, MiaPaCa-2).

Main Results:

• Compound C-9 exhibited significant inhibition against HDAC6, ROCK1, and ROCK2.
• C-9 demonstrated potent antiproliferative effects against MDA-MB-231, MiaPaCa-2, and Panc-1 cell lines, with IC50 values in the low micromolar range.
• The compound displayed notable anti-invasive and anti-migratory activities, suggesting antimetastatic potential.

Conclusions:

• Simultaneous inhibition of ROCK and HDACs is a viable therapeutic strategy for cancer treatment.
• The developed HDAC/ROCK inhibitors, particularly C-9, show promise as anticancer agents with antimetastatic properties.
• Further investigation into this class of compounds could lead to advancements in PDAC and TNBC therapy.