AP-3-84

AP-3-84 is a first-in-class small molecule inhibitor designed to selectively bind the LxCxE binding cleft of the Retinoblastoma (Rb1) protein. Developed by researchers at The Wistar Institute, it disrupts Rb1 protein-protein interactions, which are often exploited by cellular factors and viral oncoproteins to promote oncogenesis. In Acute Myeloid Leukemia (AML) models, AP-3-84 triggers cell death by activating the Unfolded Protein Response (UPR) through the PERK-eIF2a-ATF4-NOXA signaling pathway. This activation leads to mitochondrial dysfunction, lipid peroxidation, and ultimately ferroptosis. Preclinical studies have demonstrated its efficacy in reducing tumor growth in AML xenograft models without inducing significant toxicity in non-hematopoietic cells or differentiated myeloid cells.