AZD 5582

AZD 5582 is a dimeric Smac mimetic and an inhibitor of the inhibitor of apoptosis (IAP) proteins.¹ It binds to the BIR3 domains of IAP1, IAP2, and XIAP (IC₅₀s = 15, 21, and 15 nM, respectively). It disrupts the protein-protein interaction between IAP1 and caspase-9 in vitro, as well as induces degradation of IAP1 in (EC₅₀ = 0.1 nM) and reduces the growth of MDA-MB-231 breast cancer cells (GI₅₀ = <0.06 nM). AZD 5582 (0.5, 1, and 1.5 nM) also induces cleavage of caspase-3 and apoptosis in MDA-MB-231 cells. In vivo, AZD 5582 (0.1, 0.5, and 3 mg/kg) induces intratumoral apoptosis and reduces tumor volume in an MDA-MB-231 mouse xenograft model. AZD 5582 (3 mg/kg) also increases CD4⁺ T cell, spleen, thymus, bone marrow, liver, lung, and lymph node levels of HIV RNA, indicating HIV latency reversal, in a humanized mouse model of antiretroviral therapy-suppressed HIV infection.²

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1. Hennessy, E.J., Adam, A., Aquila, B.M., et al. Discovery of a novel class of dimeric Smac mimetics as potent IAP antagonists resulting in a clinical candidate for the treatment of cancer (AZD5582). J. Med. Chem. 56(24), 9897-9919 (2013).

2. Nixon, C.C., Mavigner, M., Sampey, G.C., et al. Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo. Nature 578(7793), 160-165 (2020).