Scaling the Druggability Landscape of Human Bromodomains, a New Class of Drug Targets

Abstract

Gene transcriptional activation of the human genome in response to physiological and environmental stimuli requires chromatin structure changes defined by enzymes that modify chromatin and directed by proteins that interact with chromatin in a modification-sensitive manner. This highly complex system operates with a large number of chemical modifications on chromatin (both DNA and histones) and transcription-associated proteins.1 Of these, lysine acetylation functions to facilitate chromatin opening and productive transcriptional machinery assembly required for gene activation. These activities are directed by the acetyl-lysine binding activity of the bromodomain (BrD), a fundamental molecular mechanism for gene transcriptional activation that was discovered in the structural biology study of the histone acetyltransferase (HAT) transcriptional co-activator PCAF.2 The human genome encodes a total of 61 bromodomains in 46 chromatin regulator proteins, some of which comprise multiple bromodomains.2 As a key epigenome reader, the bromodomain is almost solely responsible for binding to acetylated-lysine in histones and transcription-associated proteins, thereby orchestrating gene transcription in chromatin in an ordered fashion.2 Recent studies show that pharmacological small molecule modulation of the acetyl-lysine binding activity of BrD proteins such as the BET (Bromodomain and Extra-Terminal domain) family protein BRD4 and the HAT co-activator CBP/p300 dictates gene transcription outcome in disease models3 such as multiple myeloma, lymphoma, acute myeloid leukemia, mixed lineage leukemia, HIV-associated kidney disease, and ischemia, indicating these bromodomains as attractive drug targets for diseases including cancer and inflammation.