AZD5582

AZD5582 is an experimental, highly potent small-molecule antagonist of inhibitor of apoptosis proteins (IAPs) and a mimetic of the endogenous second mitochondrial-derived activator of caspases (SMAC), originally developed by AstraZeneca for oncology and later repurposed as a latency-reversing agent for HIV/SIV cure research.[1][3][7][9][13] Structurally, it is a bivalent SMAC mimetic that binds with low-nanomolar affinity to the BIR3 domains of cIAP1, cIAP2, and XIAP, inducing their autoubiquitination and proteasomal degradation, thereby promoting caspase activation and apoptosis, especially in tumors with high TNF and NF-κB pathway dependency.[7][9][11][12][13] Preclinical studies show antitumor activity in multiple cancer models, including pancreatic cancer, hepatocellular carcinoma, oral squamous cell carcinoma, and hematologic malignancies, often enhancing tumor cell death and modulating antitumor immunity.[3][5][6][10][12] In HIV/SIV models, AZD5582 activates noncanonical NF-κB signaling in CD4+ T cells to reverse viral latency, causing on-ART viremia and reservoir reactivation in antiretroviral-suppressed rhesus macaques and humanized mice, and it is being explored in combination with broadly neutralizing antibodies, IL-15 superagonists (N-803), vaccines, and venetoclax to reduce latent reservoirs.[1][2][3][4]