KAT2A/KAT2B (GCN5/PCAF histone acetyltransferases)

Class

Small molecule targeted protein degrader

Pathway

Chromatin acetylation / leukemic stem cell self-renewal

KAT2A (GCN5) and KAT2B (PCAF) are closely related enzymes called histone acetyltransferases (HATs). They work within large multiprotein complexes (SAGA and ATAC) that attach acetyl groups to histone proteins, the spools around which DNA is wound. This acetylation loosens the DNA-histone contact, opening chromatin so that genes can be switched on. In certain cancers, particularly acute leukemias, this chromatin-opening activity is co-opted to sustain a transcriptional program that keeps leukemic stem cells self-renewing and prevents them from maturing into non-dividing, functional blood cells. Because KAT2A and KAT2B are paralogs with overlapping functions, therapeutic strategies often need to address both simultaneously to fully disrupt this program. Rather than only blocking the enzymes' catalytic activity, a targeted protein degrader approach eliminates the entire protein, removing both its enzymatic function and any additional structural roles it plays within its complex. This mechanism is relevant broadly wherever leukemic or other cancer stem-like cells depend on aberrant chromatin regulation to maintain an undifferentiated, self-renewing state, making disruption of this dependency a rational therapeutic strategy in hematologic malignancies and potentially other cancers with similar transcriptional dependencies.