- Principal Investigator: Eloise Mastrangelo
- Â Individual Grant - MFAG
The genes for some IAPs (proteins of the inhibitor-of-apoptosis family) are known to be overexpressed in certain tumours. Indeed, IAP blocking compounds (Smac mimetics, SMs) based on the IAP antagonist Smac/Diablo are already being developed for the treatment of cancer. These antagonists target the bacuolavirus IAP Repeat (BIR) type II domain of IAPs such as XIAP (X-chromosome-linked IAP) and cIAP1/2 (cellular IAP1 and cellular IAP2), which inhibit apoptosis by different mechanisms. The project proposes a novel approach to interfering with the functions of XIAP and cIAP1/2, based on the development of protein-protein-interaction (PPI) inhibitors of the BIR1 (type I) domain of XIAP and cIAP2. The rational behind this approach is that the interaction of XIAP-BIR1 with TAB1 and that of cIAP2-BIR1 with TRAF2 lead to the formation of corresponding complex regulatory factors that drive the canonical pathway of NF-kappaB activation to inflamation and cell survival. The research group of Milano plans to follow drug design protocols with the aim to identify and optimize compounds that can be used to control the supression of apoptosis by XIAP and/or cIAP regulators. If successful the project could have a very significant on understanding control of cancer cells and on cancer treatment.
