Drug Discovery and Pharmacological Investigation of Selective Hdac1 and 2 Inhibitors as Novel Anticancer Drugs

Colorectal cancer (CRC) is the third most common type and leading cause of cancer death according to the report published by American Cancer Society. Although progression in the diagnosis and treatment have made a major impact on CRC, patients with advanced and metastatic tumors still succumb to this disease. Therefore, new drug development is an urgent medical need and histone deacetylase (HDAC) inhibitors are one of the approaches. HDACs are a class of enzymes that modify chromatin structures through regulating histone acetylation without affecting DNA sequence. Evidence has shown that class I HDAC1 and HDAC2 play important role in regulating intestinal differentiation and cancer cell apoptosis, which makes HDAC1 and 2 as important therapeutic targets for CRC treatment. Although there are numerous HDAC inhibitors in clinical trials in recent years, limitation still exist to hinder the progress of HDAC inhibitors, which are poor penetration rate in solid tumors and serious cardiac toxicity. Therefore, the goal of our project is to develop novel and selective HDAC1 and HDAC2 inhibitors as potential therapeutic anticancer agents against solid tumors without toxicity. Our team has developed 4-indolyl-N-hydroxyphenylacrylamides-based HDAC1 and 2 selective inhibitors, MPT0G352, MPT0G351 and MPT0G350. According to our preliminary data, these inhibitors exhibit significant cytotoxicity against solid tumors, especially MPT0G352 in CRC, which prompt us to further investigate the potential of these HDAC1 and 2 inhibitors as therapeutic anticancer agents. The following specific aims are proposed to achieve our objectives. Specific aim 1: To examine the anti-tumor function of MPT0G352 in colorectal cancer xenograft model. To screen the anti-proliferation, antitumor efficacy and HDAC inhibitory effect of other MPT0G352 derivatives as novel HDAC1 and HDAC2 selective inhibitors. Specific aim 2: To characterize the downstream disease-related genes regulated by MPT0G352 through HDAC2 inhibition and the anticancer mechanism of MPT0G352 in CRC. To determine the tumor inhibitory effect of MPT0G351 and MPT0G350 in vivo. Specific aim 3: To examine the anti-metastasis function of MPT0G352 in vivo in colorectal cancer lung metastasis model. To investigate the anti-metastasis mechanism of MPT0G352. Also, to further investigate the antitumor activity of MPT0G352, MPT0G351 and MPT0G350 in breast cancer and pancreatic cancer.