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Publication Abstract from PubMed

IAPs (Inhibitor of Apoptosis Proteins) are highly conserved negative regulators of apoptosis overexpressed in many cancer cells. Based on their endogenous antagonist, Smac/DIABLO, mimic compounds (Smac-mimetics, SMs) have been developed to inhibit IAPs pro-survival activity, showing promising effects in advanced phases of clinical trials. Since different IAP homologues play distinctive roles in cancer cell survival and immunomodulation, SM-induced apoptosis proceeds through diverse mechanisms. After binding to their BIR3 domain, SMs have been shown to rapidly induce auto-ubiquitylation and degradation of cellular IAPs (cIAPs), thus leading to cell death mainly by activation of the non-canonical NF-kappaB pathway. For this reason, we started the BIR3-driven design of compounds selective for cIAP1 and with reduced affinity for X-linked IAP (XIAP), in order to focus SMs anti-tumor activity on cIAPs degradation. In this work, we describe the crystal structures of the BIR3 domains of cIAP1 and XIAP, each in complex with a cIAP1-selective SM (SM130 and SM114, respectively). The two SMs displayed 23- and 32-fold higher affinity for cIAP1-BIR3 over XIAP-BIR3 in molecular displacement experiments based on fluorescence polarization. In vitro cell-based assays confirmed that both selective SMs triggered apoptosis in cancer cells with different efficiencies by inducing caspases-3, -8 and -9-independent cIAP1 degradation. The design of cIAPs-selective compounds represents an innovative approach in the field of anti-cancer drugs development, being useful to elucidate different pro-survival mechanisms, and to reduce the adverse effects of pan-IAPs compounds in cancer therapy. This article is protected by copyright. All rights reserved.

Structure-based design and molecular profiling of Smac-mimetics selective for cellular IAPs.,Corti A, Milani M, Lecis D, Seneci P, de Rosa M, Mastrangelo E, Cossu F FEBS J. 2018 Jul 28. doi: 10.1111/febs.14616. PMID:30055105^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.