Abstract
Synthetic lethality (SL) represents a new therapeutic approach for cancer treatment. DNA damage response offers the opportunity to exploit SL as proved by BRCA2 mutations that make cancer cells sensitive to PARP inhibitors (PARPi). Our team recently proposed the fully small-molecules-induced SL, which combines a small molecule inhibitor of RAD51-BRCA2 protein-protein interaction with PARPi olaparib to mimic the SL described above. Our previous studies led to ARN24089, which caused pancreatic cancer cell death in combination with olaparib, reproducing the SL paradigm. Based on these premises, the project will advance the studies on RAD51-BRCA2 small molecule inhibitors, performing structure-activity relationship studies and improving their pharmacokinetic properties, alongside the development of peptide and/or peptidomimetic inhibitors. The goal will be to evaluate their efficacy in pancreatic cancer models and validate the SL effect in vivo. A secondary goal will be to target RAD52, to explore triple synthetic lethality strategies by combining RAD52/RAD51/PARP inhibition.
Project details
Unibo Team Leader: Marinella Roberti
Unibo involved Department/s:
Dipartimento di Farmacia e Biotecnologie
Coordinator:
Università degli Studi di MILANO(Italy)
Total Unibo Contribution: Euro (EUR) 65.354,00
Project Duration in months: 24
Start Date:
18/10/2023
End Date:
28/02/2026
