Medicinal chemistry of histone deacetylase inhibitors

Abstract

Today, we are witnessing an explosion of scientific concepts in cancer chemotherapy. It has been considered for a long time that genetic instability in cancer should be treated with drugs that directly damage the DNA. Understanding the molecular basis of malignant diseases shed light on studying phenotypic plasticity. In the era of epigenetics, many efforts are being made to alter the aberrant homeostasis in cancer without modifying the DNA sequence. One such strategy is modulation of the lysine acetylome in human cancers. To remove the acetyl group from the histones, cells use the enzymes that are called histone deacetylases (HDACs). The disturbed equilibrium between acetylation and deacetylation on lysine residues of histones can be manipulated with histone deacetylase inhibitors (HDACi). Throughout the review, an effort will be made to present the mechanistic basis of targeting the HDAC isoforms, discovered selective HDAC inhibitors, and their therapeutical implications and expectations in modern drug discovery.

SIRT2i_Predictor: A Machine Learning-Based Tool to Facilitate the Discovery of Novel SIRT2 Inhibitors

“…This approach opened exciting opportunities for future usage of selective SIRT2 inhibitors in overcoming poor clinical response to the TIL (tumor-infiltrating lymphocyte) or CAR-T (chimeric antigen receptor–T cell) immunotherapies [ 14 ]. In spite of two decades of vigorous research efforts around the world and many discovered SIRT2 inhibitors, none of the described compounds have entered clinical trials, which signifies the need for novel advances in the field [ 15 ]. The most common limitations of known inhibitors includes poor selectivity, potency, or physicochemical properties [ 10 , 15 , 16 ].…”

“…In spite of two decades of vigorous research efforts around the world and many discovered SIRT2 inhibitors, none of the described compounds have entered clinical trials, which signifies the need for novel advances in the field [ 15 ]. The most common limitations of known inhibitors includes poor selectivity, potency, or physicochemical properties [ 10 , 15 , 16 ].…”

“…Most known inhibitors interfere with this catalytic mechanism by binding to the catalytic site of sirtuins positioned in the cleft between two domains ( Figure 1 C). Due to the conserved structure of the catalytic site of sirtuins, achieving the selectivity of small-molecule SIRT2 inhibitors turned out to be one of the greatest challenges in the development of this group of compounds ( Figure 1 C) [ 15 , 18 ]. Recently described pharmacological advantages of selective SIRT2 inhibition over non-selective inhibition of other isoforms of the sirtuin family, particularly sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), positioned selectivity as one of the most important objectives in development of novel SIRT2 inhibitors [ 19 ].…”

SIRT2i_Predictor: A machine learning-based tool to facilitate the discovery of novel SIRT2 inhibitors

“…14 In spite two decades of vigorous research efforts around the world and many discovered SIRT2 inhibitors, none of the described compounds entered clinical trials. 15 Achieving the selectivity of small-molecule SIRT2 inhibitors turned out to be one of the greatest challenges in development of this group of compounds. Recently described pharmacological advantages of selective SIRT2 inhibition over non-selective inhibition of other isoforms of sirtuins family, particularly sirtuins 1 (SIRT1) and sirtuin 3 (SIRT3), positioned selectivity as one of the most important objectives in development of novel SIRT2 inhibitors.…”