Abstract 19: Design and synthesis of biaryl indolyl benzamides as HDAC1-selective inhibitors via a fragment-based lead generation approach

Abstract

Histone deacetylase (HDAC) proteins are epigenetic regulatory enzymes that deacetylate protein substrates, leading to subsequent changes in cell function. HDAC proteins are implicated in cancers and several HDAC inhibitors have been approved by the FDA as anti-cancer drugs. Unfortunately, most of the FDA-approved drugs non-selectively inhibit most of the HDAC isoforms, which may lead to side effects in the clinic and limit their use on the bench top. Isoform-selective HDAC inhibitors may decrease or eliminate the side effects associated with non-selective inhibitors treatment. In addition, isoform-selective HDAC inhibitors can be used as molecular tools to study HDAC-related cancer biology. In this work, several biaryl indolyl benzamide compounds were designed and synthesized based on a fragment-based lead generation approach as potential HDAC1-selective inhibitors. The design was based on combining two different fragments from known HDAC1/2 and HDAC1/3 selective inhibitors. These fragments can discriminate against both HDAC2 and HDAC3 and possibly impart selectivity towards HDAC1. Docking studies were performed to validate the design of the inhibitors and to understand the binding of different isoform-selective inhibitors to HDAC1, HDAC2, and HDAC3. Potency and isoform selectivity of the new compounds were assessed via in vitro screening with different HDAC isoforms. All analogs showed modest selectivity for HDAC1 over HDAC2. Bnz-3 was identified as the best compound in terms of potency and selectivity. In particular, Bnz-3 displayed roughly 10- to 100-fold higher potency than the other compounds, with an IC50 value of 548 nM with HDAC1. In terms of selectivity, Bnz-3 showed about 10.6-fold selectivity for HDAC1 over HDAC2, with almost no inhibition of either HDAC3 or HDAC6. The new biaryl indolyl benzamide HDAC inhibitors represent potential lead compounds that can help to further develop more selective HDAC1 inhibitors. Citation Format: Ahmed T. Negmeldin, Mary Kay H. Pflum. Design and synthesis of biaryl indolyl benzamides as HDAC1-selective inhibitors via a fragment-based lead generation approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 19.