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Abstract
Protein arginine methyltransferase 5 (PRMT5) represents an attractive target in drug discovery due to its extensive involvement in transcriptional control, RNA processing, and other cellular pathways that are related to tumorigenesis and progression. A variety of compounds have been developed to target PRMT5. The goal of this work is to expand the diversity of chemotypes for inhibitory binding to PRMT5 or other SAM-dependent methyltransferases. As a part, we designed a series of adenosine analogs with the goal of binding to the cofactor pocket. Each compound contains a 1,2,3-triazole linkage accessed through copper catalyzed azide-alkyne cycloaddition reactions (CuAAC). Several generations of inhibitors were produced to afford an extensive structure-activity relationship with PRMT5. These compounds exhibited selectivity for PRMT5 over other enzymes within the family with lead compounds being tested in cellular assays for their anti-cancer activity. Additionally, a series of peptide chimeric probes were designed to target the dimeric interface of PRMTs. These compounds were developed as part of a proof-of-concept study around this new targeting modality and could be translated into future work with small-molecules to give more selective, tight-binding probes.