Methyltransferases catalyze the transfer of methyl groups from S-adenosylmethionine (SAM) to their substrates. Dysregulation of methyltransferases has been implicated in cancer, neurodegenerative and cardiovascular diseases. Thus, potent and selective inhibitors for individual methyltransferase are needed to dissect the roles under physiological and pathological conditions.<br/><br/>Guided by the Bi-Bi kinetic mechanism of methyltransferase, we have designed bisubstrate analogs to mimic its ternary complex by conjugating the substrate with a SAM analog. Herein, I will present our success in developing potent and selective inhibitors of protein N-terminal methyltransferase 1 (NTMT1), protein arginine methyltransferases (PRMTs), and nicotinamide N-methyltransferase (NNMT). These inhibitors displayed nM inhibitory activities for their respective target and over 100-fold selectivity against a panel of closely-related methyltransferases. Furthermore, the kinetic analysis and co-crystal structures revealed the inhibitors occupying both SAM and substrate binding sites. Moreover, we have developed cell-potent NNMT inhibitors by incorporating an unconventional SAM mimic.

Bisubstrate analogs as potent and specific inhibitors for methyltransferases

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ACS Fall 2022

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