DMPK and early tox study of a novel HDAC inhibiotr, CG200745

2617 Histone deacetylases (HDAC) which catalyse the deacetylation of histones are emerging as an important cancer target. Repression of transcription occurred by several cancer promoting mutations and chromosomal translocations leading to neoplastic transformation. HDAC inhibitor was proposed to activate of the transcription of a selected number of genes whose expression causes inhibition of tumor cell growth and induction of apoptosis. We have involved in the discovery of novel HDAC inhibitors for the treatment of cancer.
 Using proprietary structure based technologies, we have designed and optimized novel scaffolds. The optimized compounds were evaluated by various enzyme inhibitory assays, anti-proliferation assays against cancer cell lines, FACS analysis and measurement of acetylated histone accumulation. We also carried out in vitro ADME studies including metabolic stability, and CYP inhibition assays and in vivo PK studies. On the basis of these studies, we selected compounds for animal studies. The anti-tumor efficacy of the compounds was tested in the xenograft tumor model (HCT116). Many of them showed clear anti-tumor effects. CG200745 demonstrated promising efficacy among them. The IC50 of CG200745 is 9nM and the growth of various cancer cell lines such as colon, breast, stomach and liver cancer were inhibited in vitro at sub micromolar IC50. It showed growth inhibition at the dose of 10 mg/kg q.d. over period of 14 days in a regression model. From these results, it can be concluded that CG200745 is one of the novel and potent anti-tumour drug candidates. Further PK/PD studies and preclinical safety studies of CG200745 are in progress.