PPI inhibitors

Exploting synthetic lethality by a protein-protein interaction (PPI) approach.

The Target

RAD51 is an evolutionarily conserved recombinase protein central to homologous recombination (HR) an essential process for the repair of DNA double-strand breaks (DSB) and a key component of the DNA repair and DNA damage response (DDR) pathway. RAD51 is recruited to the DDR by interaction with the human tumour suppressor gene, BRCA2, at the site of DSBs where it performs DSB repair through HR.

Overexpression of the RAD51 protein is common in a wide variety of cancers (including, breast and pancreatic cancers) and moreover, the expression of RAD51 is positively correlated with resistance to radiotherapies or chemotherapies that induce DNA damage. Thus inhibitors of the RAD51-BRCA2 interaction would have broad application as novel cancer therapies.

Our research

In collaboration with the Italian Institute of Technology (IIT), the University of Bologna (UniBo) and the European Institute of Oncology (IEO), we have discovered a series of molecules that disrupt the RAD51-BRCA2 protein–protein interaction, thus mimicking the effect of BRCA2 mutations. These compounds inhibit homologous recombination in a human pancreatic adenocarcinoma cell line and the lead compound synergizes with Olaparib (a PARPi) to trigger synthetic lethality.