CPI-1612

CPI-1612 is a potent, orally bioavailable, and brain-penetrant small molecule inhibitor of the histone acetyltransferases CBP (CREB-binding protein) and p300. Developed by Constellation Pharmaceuticals, it functions as an epigenetic modulator by suppressing the acetylation of histone H3 lysine 27 (H3K27Ac), thereby downregulating the expression of genes involved in homologous recombination (HR) DNA repair, such as RAD51. Preclinical studies in glioblastoma patient-derived xenograft (PDX) models have shown that CPI-1612 can penetrate the blood-brain barrier and sensitize tumor cells to temozolomide (TMZ) by enhancing DNA damage signaling and delaying the repair of double-strand breaks. This mechanism suggests potential utility in treating high-grade gliomas and other cancers where CBP/p300 activity drives resistance or progression.