Preclinical evaluation of novel selective HDAC6 inhibitors for human cancers treatment

Background: In this project, we will develop the preclinical animal studies of azaaryl-based HDAC6 inhibitors to be anticancer candidate drug. According to our preliminary data, MPT0G211, a hit compound, shows significantly higher potency than ACY-1215 and tubastatin, which were known as HDAC6 inhibitors, in selectivity and inhibition of HDAC6 activity. Oral administration of hit compound MPT0G211 showed tumor suppression in nude mice bearing human multiple myeloma RPMI-8226 xenograft. In conclusion, MPT0G211 exhibited satisfactory therapeutic effects in human cancers. Purpose: This project aims to complete the preclinical animal studies, including in vivo pharmacological efficacy and toxicity, of HDAC6 inhibitors toward anticancer drug candidate. Method: Goals will be achieved in following aspects: (1) efficacy evaluation with pharmacodynamic functions using human hematologic and solid tumor xenograft models, murine solid tumor allograft models, and angiogenesis matrigel-plug models. (2) toxicity/safety studies and dose finding by in vitro genotoxicity and in vivo toxicity studies; (3) biomarker for understanding the mechanism of action underlying the HDAC6 inhibitors against human cancers. Anticipated results: Taken all results together, we should be able to identify a most promising compound as a new drug candidate, and transfer this project to a biotechnological company for further drug development of Industry-Academic Cooperation and Investigational New Drug (IND) application.