Type I BIR inhibitors for the regulation of NF-kB pathway

Chemoresistance challenges the development of cancer therapies and the need of improved treatments is urgent towards personalised medicine. In this context, we propose the rational design of drug candidates, based on the structural details underlying the action of the Inhibitor of Apoptosis Proteins (IAPs). IAPs are validated onco-targets, as their over-expression correlates with cancer onset and prognosis, determines the progression, metastasis and chemoresistance of the disease. IAPs regulate cell death-survival pathways, inflammation, and immunity. Targeting IAPs, in particular the Protein-Protein interactions they mediate, represents the chance to tune at molecular level the IAPs-dependent events occurring at different stages of cancer. We propose to expand the chemical space around the lead Cmp2, generating a new class of potential cancer therapics. We plan to investigate the triggered cellular pathways on a large panel of tumoral cell lines and characterize the biophysical properties underlying their action. The structure-based approach will reveal details on protein-ligands interactions and consequent conformational changes of IAPs, providing the rationale for drug lead optimization. Furthermore, the virtual screening of compounds libraries against the new IAP structural hotspots will expand the number of chemicals to be included in the development of new anti-cancer candidates.

Site: https://www.direzionescientifica.airc.it

Fund(s): Associazione Italiana per la Ricerca sul Cancro (AIRC)

Members:
Paolo Cocomazzi
Federica Cossu (Principal investigator)
Elisa Fagnani
Mario Milani