Inhibitors of Epigenetic Regulation in Cancer

Abstract

Posttranslational modifications of histones have developed into a burgeoning area of research yielding several approved drugs and clinical candidates. Histone deacetylases (HDACs) were the first of the histone-modifying enzymes to yield a clinical candidate and there are now more than four HDAC inhibitors on the market and several more in clinical trials. Despite early success, HDAC inhibitors are still an active area of research as, in efforts to reduce toxicity, investigators aim to develop inhibitors that are specific to a single HDAC or class of HDACs. As the field advanced beyond HDACs toward the discovery of histone methyltransferase (HMT) inhibitors, it became clear that each class of enzymes would require new assays and screening paradigms. The collective euchromatic histone-lysine N-methyltransferase 2 programs, for example, used a number of different biochemical assays and results were dependent on assay conditions. Pinometostat, a S-adenosylmethionine-competitive DOT1L inhibitor, was the first HMT inhibitor to enter clinical trials followed closely by several peptide competitive enhancer of zeste homolog 2 (EZH2) inhibitors. With the exception of EZH2, structure-aided design has played a large role in the development of HMT inhibitors. Bromodomain and lysine demethylase inhibitors quickly followed the HMTS with compounds in the clinic from several companies. To date bromodomains, specifically bromodomain and extra C-terminal domains, are the only reader protein with inhibitors in the clinic. A tool compound for chromodomain X has been published and these proteins are an area of active research. Despite the recent successes, there is much still to understand around histone modifications and the role these changes play in cancer. New tools for discovering key histone-modifying enzymes are being developed and new tool compounds for histone acetyltransferases and other histone-modifying enzymes are emerging in the patent literature.