Therapeutic targeting of chromatin: status and opportunities

Abstract

The molecular characterization of mechanisms underlying transcriptional control and epigenetic inheritance since the 1990s has paved the way for the development of targeted therapies that modulate these pathways. In the past two decades, cancer genome sequencing approaches have uncovered a plethora of mutations in chromatin modifying enzymes across tumor types, and systematic genetic screens have identified many of these proteins as specific vulnerabilities in certain cancers. Now is the time when many of these basic and translational efforts start to bear fruit and more and more chromatin‐targeting drugs are entering the clinic. At the same time, novel pharmacological approaches harbor the potential to modulate chromatin in unprecedented fashion, thus generating entirely novel opportunities. Here, we review the current status of chromatin targets in oncology and describe a vision for the epigenome‐modulating drugs of the future.

Structural characterization of dicyanopyridine containing DNMT1-selective, non-nucleoside inhibitors

“…Methylation can occur on DNA, RNA, and proteins, and the development of cancer therapeutics targeting S-adenosyl-L-methionine (SAM)-dependent methylation has been pursued widely. Consequently, drug development targeting methylation is proceeding rapidly, and several DNA hypomethylating agents have been US Food and Drug Administration (FDA) approved for the treatment of specific cancers (Jarrold and Davies, 2019;Siklos and Kubicek, 2021;Yankova et al, 2021;Yoo and Jones, 2006).…”

DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro

“…To investigate this possibility, more specific inhibitors could be used in future studies. Class-I specific HDAC inhibitors are available for such studies, but inhibiting HDAC1 or other specific class-I HDACs remains a challenge ( Schölz et al, 2015 ; Eckschlager et al, 2017 ; Shortt et al, 2017 ; Pride and Summers, 2018 ; Hess et al, 2022 ; Siklos and Kubicek, 2022 ). Interestingly, recent efforts have led to the development of more selective HDAC inhibitors, some of which inhibit certain class-I HDACs more than others ( Yang et al, 2019 ; Hess et al, 2022 ; Siklos and Kubicek, 2022 ).…”

Comparative Study of Adenosine Analogs as Inhibitors of Protein Arginine Methyltransferases and a Clostridioides difficile-Specific DNA Adenine Methyltransferase

“…SAM is involved in a wide range of biochemical reactions including (but not limited to) transmethylation reactions, , radical SAM reactions, − polyamine biosynthesis, and SAM-sensing riboswitches. , SAM-dependent methyltransferases (MTases) catalyze methyl transfers onto a wide variety of substrate molecules, including both macromolecules (DNA, RNA, polysaccharides, lipids, and proteins) and micromolecules (such as catechol, arsenic, histamine, nicotinamide, and thiopurine). Given the significance of epigenetic methylation of macromolecules in cancer, immunity, cardiovascular and many other diseases, as well as methylation of anticancer drugs such as thiopurine, , SAM-dependent MTases are increasingly becoming therapeutic targets. − …”

“…Given the significance of epigenetic methylation of macromolecules in cancer, immunity, cardiovascular and many other diseases, as well as methylation of anticancer drugs such as thiopurine, 12 , 13 SAM-dependent MTases are increasingly becoming therapeutic targets. 14 − 19 …”