Protein methyltransferases (PMTs) orchestrate epigenetic pathways through diverse posttranslational methylation. The errors in the process have been implicated in many abnormalities including neurological disorders and cancer. In contrast, few target-specific PMT inhibitors have been reported so far. It is of great challenge to develop PMT inhibitors aiming at potency and specificity, given highly conserved SAM-binding pockets and unstructured substrate-binding sites of PMTs. We therefore leverage several unconventional strategies to develop PMT inhibitors within the scope of our interest in PMT perturbation and cancer therapy. We designed sinefungin analogues against a collection of human PMTs and identified structurally-distinct sinefungin scaffolds that can selectively bind a subset of PMTs such as SETD2 and CARM1. We also developed novel scaffolds to inhibit SET8 through covalent modification. The modes of inhibition and implementation of these inhibitors will be discussed as well.

Unconventional chemical tools to interrogate protein methyltransferases

249th National Meeting (2015)

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