Development of Novel Proteolysis Targeting Chimeras (PROTACs) for PRMT1 Degradation

The aim of this project is to synthesise the first PROTAC that selectively degrades the cancer-causing protein PRMT1. The development of such a PROTAC has the potential of strongly contributing to PRMT1-associated cancer treatments.
Type I protein arginine methyltransferases (PRMT1s) have been shown to have increased expression in human breast, colon, and bladder cancer. Previous studies have shown that the inhibition of the PRMT1 in cell and animal models of cancer caused the reduction in tumour size and growth.
Herein, we propose that the degradation of PRMT1 will have a more profound therapeutic effect in cancer models than PRMT1 inhibition by active-site occupancy, because targeted protein degradation can provide greater and more sustained loss of PRMT1 activity.
PROTACs (proteolysis-targeting chimeras) are organic compounds that promote the degradation of a specific protein of interest. This technology works by inducing the proximity between PRMT1 and an E3 ligase, which will then transfer a ubiquitin unit to the target protein. These PROTACs will be heterobifunctional molecules that will recognise both an E3 ligase and PRMT1, thus favouring the transfer of the ubiquitin group, and hence increasing PRMT1 degradation.
The project will involve the organic synthesis of novel compounds and their biological evaluation in-vitro.