KAT6A/KAT6B and KAT7

Class

small-molecule inhibitor of the histone lysine acetyltransferases KAT6A, KAT6B, and KAT7

Pathway

inhibiting KAT6A/B and KAT7 disrupts histone lysine acetylation, altering transcriptional programs including cell cycle, MYC, estrogen receptor, and lineage-associated genes in solid tumors

KAT6A, KAT6B, and KAT7 (also called MOZ, MORF, and HBO1) are enzymes of the MYST family of histone lysine acetyltransferases. They attach acetyl groups to specific lysine residues on histone proteins, loosening the packaging of DNA so that nearby genes can be transcribed. Through this activity they help control cell cycle progression, MYC-driven proliferation programs, estrogen receptor signaling, and genes that determine what type of cell a given cell becomes. In several solid tumors, this acetylation machinery is co-opted to sustain abnormal proliferation and to block normal differentiation, keeping malignant cells locked in a proliferative, immature state. Because these three enzymes can act redundantly at overlapping regions of chromatin, inhibiting all three together is intended to more completely shut down the transcriptional programs a tumor relies on, rather than leaving an escape route through an unaffected paralog. Small-molecule inhibitors that block the catalytic acetyltransferase domain aim to lower histone acetylation at these gene sites, reducing output from oncogenic pathways such as MYC and estrogen receptor signaling and pushing cells toward cell cycle exit or differentiation. This mechanism is being explored broadly across hormone-receptor-driven and other solid tumor types where these chromatin regulators support tumor maintenance.