Aim: Histone deacetylase (HDAC) inhibitors are a class of drugs that modulate transcriptional activity in cells and are known to induce cell-cycle arrest and angiogenesis, the major components of tumor cell proliferation.The aim of the present study was to characterize a novel hydroxamic acid-based HDAC inhibitor, PAT-1102, and determine its efficacy and tolerability in pre-clin. models.Materials and Methods: HDAC enzyme inhibition was measured using HeLa cell nuclear extracts, and recombinant HDAC enzymes.Antiproliferative activity was assessed in a panel of cancer cell lines.Histone hyper-acetylation status and p21 induction were assessed in HeLa cells by immunoblotting.The effect on apoptosis was tested by caspase-3 activation and detection of cleaved poly-ADP ribose polymerase (PARP).Single-dose pharmacokinetics of the compound were assessed in BALB/c mice following oral and i.v. administration.Antitumor efficacy was evaluated in tumor-bearing mice established from lung and colorectal cancer cells (A549 and HCT116, resp.).Results: PAT-1102 demonstrated potent HDAC-inhibitory activity and growth-inhibitory properties against a panel of cancer cell lines.The optimized compound PAT-1102 exhibits good aqueous solubility, metabolic stability and a favorable pharmacokinetic profile.Once-daily oral administration of PAT-1102 resulted in significant antitumor activity and was well-tolerated in mice.Conclusion: Our results indicate that PAT-1102 is a novel, potent, orally available HDAC inhibitor with antiproliferative activity against several human cancer cell lines and antitumor activity in mouse xenograft models.Based on the pre-clin. efficacy and safety profile of PAT-1102, the compound demonstrates significant potential for evaluation as a novel drug candidate for cancer therapy.
