Drug Discovery and Pharmacological Study of Novel pan-HDAC Inhibitors as Anti-Angiogenic Drugs

Histone deacetylase (HDAC) are the enzymes that catalyze the deacetylation of histones and nonhistone proteins at the lysine residue therefore epigenetically regulate chromatin architecture and gene expression. Accumulative evidence have suggested that overexpression of HDAC induce angiogenesis by negative regulation of tumor suppressor genes. Inhibitors targeting HDAC have been shown to reverses aberrant epigenetic status and exhibits potent antitumor activities by inducing a broad range of effects on cancer cells, including cell cycle arrest and apoptosis. Numbers of diverse HDAC inhibitors were shown to have potential anti-angiogenic effects, such as SAHA (suberoylanilide hydroxamic acid) and depsipeptide (Romidepsin, FK-228), have recently been approved to treat cutaneous lymphoma by the Food and Drug Administration (FDA) in 2006 and 2009, respectively. However, HDAC is a novel target for today’s drug discovery and development, and many investigators are intensively developing various structures of HDAC inhibitors. In the previous study, our team has developed a new pan-HDAC inhibitor, MPT0E028, which will submit IND for an anticancer drug to FDA and TFDA in early 2014. In this project will follow previous successful methods to discover HDAC inhibitors from the derivatives of 1-arylsulfonyl-5-(hydroxyacrylamide)indoles and alkylaminobenzenesulfonamides with anti-angiogenic effects. From our preliminary data, both derivatives have potent anti-proliferative effects in human umbilical vein endothelial cells (HUVECs) as well as the inhibitory effects on tumor growth in vivo. The specific aims of this project include the following: Specific Aim 1 is design of potential small molecular inhibitors of HDAC. The first step in the drug discovery effort was the structure-based design. We will use matrigel-plug models as an initial in vivo screening to provide the efficacy. Aim 2. Follow up primary screen of HDAC inhibitors with secondary biochemical, pharmacological, and cell based assays to confirm hits. The mechanism of action will be verified by in vivo animal models and confirmed by immunohistochemistry methods. Aim 3. The establishment of optimized xenograft animal models is crucial for the success of HDAC inhibitors. To understand complex biological phenomena and the process of disease development, it requires the application of animal model and proper data analysis. We will also observe efficacy of the optimized compounds in combination with clinical therapies in cancer in vitro and in vivo, and determine the pharmacokinetic experiment in vivo. However, the goal of this proposal is to design new HDAC inhibitors that can be used to explore the basic biology of HDAC and improve the selectivity of presently discovered active HDAC inhibitors that are currently being developed as medications for angiogenesis-related diseases, such as cancer.