ACY-957

ACY-957 is an orally bioavailable small-molecule biaryl aminobenzamide inhibitor that selectively targets class I histone deacetylases HDAC1 and HDAC2 with nanomolar potency and over 50–100-fold selectivity versus HDAC3, leading to increased histone acetylation and broad epigenetic reprogramming in hematopoietic and leukemia cells.[3][4][5][7][10] Developed by Acetylon Pharmaceuticals as a preclinical epigenetic modulator, ACY-957 induces fetal hemoglobin (HbF) by upregulating γ-globin (HBG) transcription through HDAC1/2 inhibition and GATA2 activation in erythroid progenitors, suggesting potential utility for sickle cell disease and β-thalassemia, while also demonstrating antiproliferative, pro-differentiation, and pro-apoptotic activity in acute myeloid leukemia and diffuse large B-cell lymphoma models.[3][4][6][8] The compound has been used extensively as a tool HDAC1/2-selective inhibitor in vitro and in vivo but has not advanced into clinical development.