AIRC MFAG2021 Cossu (DFM.AD004.317)

Thematic area

Physical sciences and technologies of matter

Project area

Structure responsible for the research project

Institute of biophysics (IBF)

Project manager

FEDERICA COSSU
Phone number: 02 50314896
Email: cossu.federica@cnr.it

Abstract

BACKGROUND:Inhibitors of apoptosis proteins (IAPs) constitute a family of conserved proteins whose over-expression enhances cell survival and resistance to anticancer agents. IAPs act as E3 ligases, being recruited to macromolecular complexes for downstream regulation of the NF-ºB pathway, after stimulation of TNFreceptor with TNF-alpha. Type I BIR (Baculovirus IAP repeat) domains from different IAPs (mainly XIAP and cIAPs) has been recognized as a pivotal platform for the assembly of such complexes. PRELIMINARY: For this reason, we started the rational design, synthesis and optimization of new cell death-inducing compounds able to target the "hot-spots" of IAP BIR1 domains (cIAP2- BIR1/TRAF2) and hamper crucial pro-survival PPIs in cancer cells. Such strategy represents an innovative approach to cIAPs inhibition in order to promote apoptosis. In vitro cell-free and cell-based assays demonstrated that: (i) two candidate compounds belonging to different chemical classes are able to bind homologous BIR1 domains with low micromolar affinity and disrupt/perturb the assembly of isolated BIR1-containing macromolecular complexes; (ii) one candidate hit significantly decreased cancer cell

Start date of activity

02/01/2022

Keywords

anticancer agents, apoptosis, BIR1 domains

Last update: 22/12/2024