C14

Inhibitors of histone deacetylases (HDAC) are emerging as an exciting new class of anti-cancer drugs that arrest tumor growth by modulating the expression of a number of genes involved in cell proliferation, cell cycle progression, cell survival and differentiation.
 SB939 is a novel, potent and selective HDAC inhibitor with improved efficacy and tolerability compared to other HDAC inhibitors currently in clinical trials. SB939 inhibits class I and II HDAC enzymes with high selectivity over other zinc binding enzymes. SB939 exerts potent anti-proliferative and apoptosis-inducing effects against a broad range of human tumor cell lines and primary cells from cancer patients, with highest potencies against malignancies of haematological origin. In cancer cell lines, SB939 increases acetylation of histone3 (H3) and tubulin, increases the expression of p21, and reduces phosphorylation of retinoblastoma protein (pRb), resulting in cell cycle arrest and leading to apoptotic cell death. SB939 has excellent pharmacokinetic and pharmacodynamic (PK/PD) properties and tolerability after oral administration in preclinical species. SB939 is a highly soluble and permeable compound and does not undergo active P-glycoprotein transport. It significantly and dose-dependently inhibits tumor growth in mouse models of human haematological and solid tumors. In a nude mice model of colorectal cancer (HCT116), enriched tumor concentrations of SB939 and increased acetylation of histone H3 were observed in tumor tissue for up to 24 h after a once daily oral dose (50-100 mg/kg), confirming long-lasting and potent target inhibition. PK/PD parameters that best described the anti-tumor activity of HDAC inhibitors in the HCT116 tumor model have been identified and will be used to help select the dose of SB939 in Phase I clinical trials.
 SB939 is currently in Phase I clinical studies in Singapore and North America after having completed pre-clinical development.

First AACR Centennial Conference on Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

American Association for Cancer Research
2007