title: Discovery of PAT-1102, a novel, potent and orally active histone deacetylase inhibitor with antitumor activity in cancer mouse models.
abstract: OBJECTIVE
  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-clinical models.
  
  
  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 intravenous administration. Antitumor efficacy was evaluated in tumor-bearing mice established from lung and colorectal cancer cells (A549 and HCT116, respectively).
  
  
  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.
  
  
  CONCLUSIONS
  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-clinical efficacy and safety profile of PAT-1102, the compound demonstrates significant potential for evaluation as a novel drug candidate for cancer therapy.
authors.affiliation: Anthem Biosciences Pvt. Ltd., Bangalore, India.
authors.forename: Jagadheshan
authors.initials: J
authors.lastname: Hiriyan
authors.affiliation: Anthem Biosciences Pvt. Ltd., Bangalore, India.
authors.forename: Prasad
authors.initials: P
authors.lastname: Shivarudraiah
authors.affiliation: Anthem Biosciences Pvt. Ltd., Bangalore, India.
authors.forename: Govindarajulu
authors.initials: G
authors.lastname: Gavara
authors.affiliation: Micro Therapeutics Research Labs Pvt. Ltd., Chennai, India.
authors.forename: Pazhanimuthu
authors.initials: P
authors.lastname: Annamalai
authors.affiliation: DSK Innosciences, Kelamangalam, Hosur, India.
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Natesan
authors.affiliation: Anthem Biosciences Pvt. Ltd., Bangalore, India.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Sambasivam
authors.affiliation: Anthem Biosciences Pvt. Ltd., Bangalore, India sunilkumar.s@anthembio.com.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Sukumaran
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D045325:HCT116 Cells; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D020128:Inhibitory Concentration 50; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C000595881:PAT-1102; D014230:Triazoles; D000077337:Vorinostat
keywords: HDAC inhibitor; Histone deacetylation; PAT-1102; vorinostat