A detail survey and analysis of selectivity criteria for indole-based histone deacetylase 8 (HDAC8) inhibitors

Histone deacetylases (HDACs) are attractive therapeutic targets due to their involvement in a variety of human diseases including cancer. All FDA-approved HDAC-targeting drugs are pan-HDAC inhibitors and these drugs possess unwanted effects at therapeutic doses. In this scenario selective HDAC8 inhibition can offer beneficial therapeutic effects. Here, HDAC8 inhibition and selectivity over other HDACs are discussed for indole-based HDAC inhibitors (iHDAC) on the basis of extensive literature review and molecular modeling studies. Indole scaffold is one of the main contributors in FDA approved anticancer drugs, and discovery of a potent and selective indole-based iHDAC8 (PCI-34051) created huge attention in the development of indole-based iHDAC. Our critical analysis has given important insights into the specific structural features of iHDAC8 and selectivity over other HDACs (HDAC1, 2, 3 and 6). The present work also aims at predicting/screening selective inhibitors against HDAC8 with the QAAR models. The developed QAAR models may be used in future design as well as the prediction of HDAC8 inhibitory activities of indole derivatives and others.