HDAC3 is a potential validated target for cancer: An overview on the benzamide-based selective HDAC3 inhibitors through comparative SAR/QSAR/QAAR approaches

Deacetylation of histones by histone deacetylase 3 (HDAC3) is involved in apoptosis, cellular progression and DNA damage. Due to the overexpression of HDAC3 in a variety of cancers, it is implicated to be a crucial validated target for cancer. Therefore, HDAC3 selective inhibitors have roles to play in combating these cancers. Nowadays, compounds comprising benzamide functionality as zinc binding group (ZBG) have been emerged out to be highly effective and selective HDAC3 inhibitors. In this article, QSAR and QAAR studies have been conducted on diverse benzamide-derived HDAC3 inhibitors as the first initiative to explore the designing strategies of higher active and selective HDAC3 inhibitors over HDAC1 and HDAC2. QSAR models reveal that molecular size and shape along with the steric effect should have to be optimized to achieve higher HDAC3 inhibition. QAAR models reflect that modification/substitution at the benzamide scaffold should be optimized in such a way so that these molecules possess lower steric bulk along with nonpolar features for achieving higher HDAC3 selectivity over HDAC1 and HDAC2. However, the importance of spiro hydrophobic cap group, as well as electron withdrawing fluorine group at the benzamide scaffold, should be well-accounted for retaining higher HDAC3 selectivity over HDAC1. Moreover, less polar and less hydrophobic benzamides are preferred for HDAC3 selectivity over HDAC2. This detailed structural exploration will surely unveil a new vista of designing highly potent and selective benzamide-based HDAC3 inhibitors that may be a crucial weapon to battle against a variety of cancers.