The search for novel inhibitors of coactivator-associated arginine methyltransferase 1

Coactivator-associated arginine methyltransferase 1 (CARM1) is a member of the protein arginine methyltransferase (PRMT) family of enzymes, and is also known as PRMT4. PRMTs catalyse the transfer of methyl groups from S-adenosyl-L-methionine (SAM) to the side chain of arginine residues in substrate proteins. The dysregulation of CARM1 contributes to the onset and progression of breast and prostate cancer. For this reason, CARM1 is a target for inhibition, yet CARM1 inhibitors to date either lack selectivity or fail to show anti-proliferative effects in cells. This work aims to identify novel small molecules that can be further developed to inhibit CARM1 activity in cancer cells. Using the crystal structure (2Y1X) of the CARM1 catalytic domain in complex with CMPD-2 and S-adenosyl-L-homocysteine as a model for downstream screening, a computer-aided drug discovery and design (CADD) pipeline was developed, enabling docking to identify novel inhibitors. Over 76,600 compounds alongside known CARM1 inhibitors were screened using the industry standard proprietary software suite Accelrys Discovery Suite 4.5®. LibDock and CDOCKER algorithms were deployed independently and in series. Subsequently, a P81 filter-binding assay assessed the top hits from the in silico screening for CARM1 inhibition in vitro to generate IC50 values. A lead CARM1 inhibitor, Diamine 12 was used as a positive control, which scored highly with LibDock and CDOCKER and had an IC50 value of 1.3±1 µM with the P81 filter-binding assay. Top-ranked hits identified using Accelrys® showed some binding interactions in the arginine-binding cavity yet little to no activity in vitro. The work here fundamentally addresses the development of a workflow that provides a platform for discovery consisting of in vitro and in silico screening methods. Future work will involve expanding on the findings here to identify novel CARM1 inhibitors to be developed into therapeutic agents for the treatment of breast and prostate cancers.Pharmaceutical Sciences, Faculty ofGraduat