Identification and development of a small molecule probe for HNMT

National Center For Advancing Translational Sciences

Investigators

Abstract

Small molecule methyltransferases (SMMTases) catalyze the transfer of a methyl group from S-adenosylmethionine (SAM) to the N-, O-, or C- atom of a small metabolite. SMMTases share a Rossman-like fold with a conserved SAM-binding motif, but act on a diverse array of substrates. Many SMMTase substrates, such as norepinephrine and histamine, act in key signaling pathways. Others SMMTases play a olein in the clinic. Several SMMTase deficiencies are recognized by GARD as rare diseases. Despite their importance in regulating key biological processes, SMMTases have gone largely ignored as candidates for therapeutic or probe development. SMMTases are ideal candidates for target class profiling. During this reporting period, the collaborative team screened the small molecule methyl transferase HNMT (histamine N-methyl transferase) against several compound collections. Medicinal chemistry optimization is ongoing to improve potency and drug-like properties of identified hit series, and X-ray co-crystallization work is underway to aid in structure-based drug design.