Epigenetic alterations (i.e. that do not involve changes in the underlying DNA sequence) of chromatin are known to cause gene transcription and gene expression disorders connected to tumorigenesis. Histone deacetylases (HDACs), a group of epigenetic enzymes that modulate chromatin activity by removing acetyl groups from the lysine residues of histones, have received worldwide attention as anticancer targeted molecules. Specifically, class III HDACs (SIRT1 - 7) have emerged as one of the most important cancer targeted molecules. Notably, SIRT 1 and 2 are expected to be potential biomarkers for tumorigenesis since they are proven to be over-expressed in cancer cells. SIRT1 regulates several tumor suppressor genes such as p53 and forkhead box (FOXO) whereas SIRT2 regulates a G2/M mitotic checkpoint and 1-tubulin stability. Interestingly, all the HDAC inhibitors currently being evaluated as anticancer drugs in clinical trials act as either class I specific or class I and II non-specific inhibitors. Since SIRTs possess the same biological functions as classical HDACs, SIRT inhibitors have great potential to be anticancer leads with a new mode of action. Despite clear evidence that SIRTs are anticancer targeted molecules, development of SIRT inhibitors is especially lacking when compared with that of classical HDAC inhibitors. Furthermore, no SIRT inhibitors have been evaluated as anticancer leads in clinical trials. This research proposal is an innovative approach to discover class III specific HDAC inhibitors from rare marine-derived actinomycetes.
The specific aims of this research plans are as follows: (1) Create crude extract libraries and highly fractionated HPLC peak libraries from rare marine-derived actinomycetes. (2) Identify and characterize novel Sir2 inhibitors using a yeast assay. (3) Apply a SIRT enzyme assay to chemical libraries and pure compounds.
Relevance to public health the development of isoform-specific HDAC inhibitors is an exciting approach for the discovery of novel anticancer drugs. Class III HDAC inhibitors are promising anticancer leads with a new mode of action. The expected outcome will directly contribute to human healthcare by offering new treatment option against cancer.
|Chen, Yi-Pei; Catbagan, Chad C; Bowler, Jeannette T et al. (2014) Evaluation of benzoic acid derivatives as sirtuin inhibitors. Bioorg Med Chem Lett 24:349-52|