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Designing Smac-mimetics as antagonists of XIAP, cIAP1, and cIAP2 |
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| Authors: | Cossu Federica Mastrangelo Eloise Milani Mario Sorrentino Graziella Lecis Daniele Delia Domenico Manzoni Leonardo Seneci Pierfausto Scolastico Carlo Bolognesi Martino |
| Institution: | a Department of Biomolecular Sciences and Biotechnology, University of Milano, Via Celoria 26, I-20133 Milano, Italy b CNR, Istituto Nazionale Fisica della Materia (INFM), Via Celoria 26, I-20133 Milano, Italy c Department of Experimental Oncology, Fondazione IRCCS, Istituto Nazionale dei Tumori, Via Venezian 1, I-20133 Milano, Italy d CNR, Istituto di Scienze e Tecnologie Molecolari (ISTM), Via Golgi 19, I-20133 Milano, Italy e Centro Interdisciplinare Studi bio-molecolari e applicazioni Industriali (CISI), University of Milano, Via Venezian 21, I-20133 Milano, Italy f Department of Organic and Industrial Chemistry, University of Milano, Via Venezian 21, I-20133 Milano, Italy |
| Abstract: | Inhibitor of apoptosis proteins (IAPs) such as XIAP, cIAP1, and cIAP2 are upregulated in many cancer cells. Several compounds targeting IAPs and inducing cell death in cancer cells have been developed. Some of these are synthesized mimicking the N-terminal tetrapeptide sequence of Smac/DIABLO, the natural endogenous IAPs inhibitor. Starting from such conceptual design, we generated a library of 4-substituted azabicyclo5.3.0]alkane Smac-mimetics. Here we report the crystal structure of the BIR3 domain from XIAP in complex with Smac037, a compound designed according to structural principles emerging from our previously analyzed XIAP BIR3/Smac-mimetic complexes. In parallel, we present an in silico docking analysis of three Smac-mimetics to the BIR3 domain of cIAP1, providing general considerations for the development of high affinity lead compounds targeting three members of the IAP family. |
| Keywords: | XIAP X-linked Inhibitor of Apoptosis Protein cIAP cellular IAP BIR domain baculoviral IAP Repeat domain Smac-DIABLO second mitochondria-derived activator of caspases (Smac)-Direct IAp binding protein with LOw pI |
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