Chemical Epigenetics: The Impact of Chemical and Chemical Biology Techniques on Bromodomain Target Validation

Abstract

Epigenetics is currently the focus of intense research interest across a broad range of disciplines due to its importance in a multitude of biological processes and disease states. Epigenetic functions result partly from modification of the nucleobases in DNA and RNA, and/or post‐translational modifications of histone proteins. These modifications are dynamic, with cellular machinery identified to modulate and interpret the marks. Our focus is on bromodomains, which bind to acetylated lysine residues. Progress in the study of bromodomains, and the development of bromodomain ligands, has been rapid. These advances have been underpinned by many disciplines, but chemistry and chemical biology have undoubtedly played a significant role. Herein, we review the key chemistry and chemical biology approaches that have furthered our study of bromodomains, enabled the development of bromodomain ligands, and played a critical role in the validation of bromodomains as therapeutic targets.

Rewiring the Epigenetic Networks in MLL-Rearranged Leukemias: Epigenetic Dysregulation and Pharmacological Interventions

“…The advent of massive parallel sequencing technologies and genetic screening technologies such as RNAi and CRISPR-Cas9 has enabled biomedical scientists to uncover cancer vulnerabilities and discover new therapeutic targets for cancer treatments in a high-throughput manner (Shalem et al, 2015; McDonald et al, 2017; Meyers et al, 2017; Tsherniak et al, 2017). With the emergence of dTAG technology, cancer researchers are equipped with an acute proteasome-mediated protein knock-out method for interrogating biological function and early validation of therapeutic targets, before a valid binding ligand is identified (Winter et al, 2015; Nabet et al, 2018; Mayor-Ruiz and Winter, 2019; Schiedel et al, 2019). With such genetic and chemical discovery tools in hand, we foresee that researchers are empowered to discover and validate important therapeutic targets to treat diseases driven by epigenetic abnormalities such as MLL -r leukemias.…”

Hypoxia-activated pro-drugs of the KDAC inhibitor vorinostat (SAHA)

“…[7][8][9] Bromodomain-containing proteins function by promoting the formation of proteinprotein and protein-chromatin interactions, which often affect gene transcription. 10,11 Lysine deacetylating and deacylating enzymes are subdivided into two mechanistically-distinct classes. The sirtuin enzymes (Sirt1-7) are NAD + dependent, while the KDACs (KDAC1-11) have a Zn 2+ -dependent mechanism.…”

Discovery of a hidden transient state in all bromodomain families

“…Human bromodomains (BDs) are important epigenetic regulators, recognizing or "reading" acetylation marks in histone tails. 17 These domains are part of larger proteins that may also include enzymatic domains to modify chromatin structure, or binding domains that can serve as platforms to recruit and activate transcription factors. 18 Their central role make BD-containing proteins pivotal to regulate gene expression, representing crucial targets for the treatment of several diseases.…”