KAT6A / KAT6B

Class

KAT6 inhibitor (small molecule); INN prifetrastat

Pathway

Epigenetic regulation of ER-driven transcription (developed for CDK4/6-inhibitor-resistant HR+/HER2- breast cancer, also tested more broadly in solid tumors)

KAT6A and KAT6B (also called MOZ and MORF) are enzymes known as lysine acetyltransferases. Their normal role is to add acetyl chemical groups onto histone proteins, the spool-like proteins around which DNA is wound. This acetylation loosens chromatin structure and allows the transcriptional machinery to access specific genes, thereby regulating when and how strongly those genes are expressed. In several cancers, particularly hormone receptor-positive breast cancer, this chromatin-opening activity is co-opted to sustain the transcriptional program driven by the estrogen receptor, a nuclear protein that promotes tumor cell growth in response to estrogen. Because estrogen receptor signaling can persist even after tumors become resistant to standard treatments such as CDK4/6 inhibitors, drugs that block KAT6A and KAT6B are being explored as a way to shut down this transcriptional support system directly at the chromatin level rather than at the receptor itself. Both paralogs are inhibited together because they can substitute for one another within similar protein complexes, so blocking only one might leave the transcriptional program largely intact. This mechanism is relevant broadly across solid tumors where transcriptional dependencies on chromatin regulators contribute to disease progression or treatment resistance.