Histone lysine acetyltransferase inhibitors: an emerging class of drugs for cancer therapy

• Published in: Trends in pharmacological sciences (Regular ed.) Vol. 45; no. 3; pp. 243 - 254
• Main Authors: White, Jeffrey, Derheimer, Frederick A., Jensen-Pergakes, Kristen, O’Connell, Shawn, Sharma, Shikhar, Spiegel, Noah, Paul, Thomas A.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2024
• Subjects: Advanced Basic Science; CREBBP; EP300; Histone Acetyltransferases - genetics; Histone Acetyltransferases - metabolism; Histones - metabolism; Humans; KAT2A; KAT6A; KAT7; Lysine - metabolism; lysine acetyltransferases; Lysine Acetyltransferases - chemistry; Lysine Acetyltransferases - genetics; Lysine Acetyltransferases - metabolism; Neoplasms - drug therapy; EP300; CREBBP; KAT2A; KAT7; KAT6A; lysine acetyltransferases
• ISSN: 0165-6147; 1873-3735; 1873-3735
• DOI: 10.1016/j.tips.2024.01.010

Due to their important function in cancer, lysine acetyltransferases (KATs) are an emerging class of drug targets.Small-molecule KAT inhibitors have been discovered targeting bromodomains and acetyl-CoA catalytic domains.CREB binding protein (CREBBP)/EP300 bromodomain and KAT6A/B catalytic inhibitors are in early clinical development.New approaches to degrade KATs or redirect their activity to unique promoters offer new targeting strategies and the potential to specifically target KAT activity in cancer tissues. Lysine acetyltransferases (KATs) are a family of epigenetic enzymes involved in the regulation of gene expression; they represent a promising class of emerging drug targets. The frequent molecular dysregulation of these enzymes, as well as their mechanistic links to biological functions that are crucial to cancer, have led to exploration around the development of small-molecule inhibitors against KATs. Despite early challenges, recent advances have led to the development of potent and selective enzymatic and bromodomain (BRD) KAT inhibitors. In this review we discuss the discovery and development of new KAT inhibitors and their application as oncology therapeutics. Additionally, new chemically induced proximity approaches are presented, offering opportunities for unique target selectivity profiles and tissue-specific targeting of KATs. Emerging clinical data for CREB binding protein (CREBBP)/EP300 BRD inhibitors and KAT6 catalytic inhibitors indicate the promise of this target class in cancer therapeutics. Lysine acetyltransferases (KATs) are a family of epigenetic enzymes involved in the regulation of gene expression; they represent a promising class of emerging drug targets. The frequent molecular dysregulation of these enzymes, as well as their mechanistic links to biological functions that are crucial to cancer, have led to exploration around the development of small-molecule inhibitors against KATs. Despite early challenges, recent advances have led to the development of potent and selective enzymatic and bromodomain (BRD) KAT inhibitors. In this review we discuss the discovery and development of new KAT inhibitors and their application as oncology therapeutics. Additionally, new chemically induced proximity approaches are presented, offering opportunities for unique target selectivity profiles and tissue-specific targeting of KATs. Emerging clinical data for CREB binding protein (CREBBP)/EP300 BRD inhibitors and KAT6 catalytic inhibitors indicate the promise of this target class in cancer therapeutics.