Development of selective HDAC (histone deacetylase) inhibitors has become a trend of recent research, especially the development of HDAC6 inhibitors. In 2010, tubastatin A was found exhibiting marked inhibitory effect of HDAC6, but having weak antiproliferative activity. ACY-1215 was reported exhibiting potent HDAC6 inhibitory activity. In 2012, ACY-1215 has entered clinical trials for the treatment of multiple myeloma. In order to develop selective HDAC6 inhibitors, this project is aimed to synthesize a series of heterocycle-substituted N-hydroxybenzamides and its regioisomers. The first year results indicated that the lead MPT0G211 exhibited significant HDAC6 enzymatic activity and selectivity. It also significantly inhibits tumor growth in in vivo xenograft models, especially for hematologic malignancies. Therefore, this series of compounds do have potential to develop as potent anti-cancer molecules with HDAC6 inhibition activity. In an attempt to enhance the research breadth and to develop a potent anti-cancer small molecule which is able to enter clinical trials, this three-years project will includes structural exploration and optimization, investigation of early-PK profiles, establishment of pharmacological activity, biological activity mechanism studies and optimized synthetic approach for production. We will identify the drug candidate towards the further GLP preclinical toxicology evaluation.
|Effective start/end date||1/1/15 → 12/31/15|