DEVELOPING SELECTIVE DRUG LIKE INHIBITORS OF GLYCINE AND HISTAMINE N-METHYL TRANSFERASES

Authors

• S Sharma
• S Karavadhi
• VK Chenniappan
• D Moya
• JH Shrimp
• L Crawford
• QM Hanson
• N Hoxie
• H Sun
• M Shen
• MD Hall
• S Patnaik

Abstract

Small molecule methyltransferases (SMMTase) are an understudied class of methyltransferases. These enzymes catalyze the transfer of a methyl group from the universal methyl donor S-adenosylmethionine (SAM) to their substrates and generate S-Adenosyl-L-homocysteine (SAH). This modification has recently gained much attention for its roles in epigenetics and cancer. We utilized a target class profiling strategy where the MTase-GloTM Methyltransferase Assay was adapted for high throughout assay platform to screen diverse SMMTases against a library of 27,574 unique small molecules. This effort enabled the identification of a novel GNMT and HNMT-selective chemotypes.
GNMT is a liver cytosolic enzyme that regulates the SAM/SAH balance and its deficiency linked to liver and pancreatic cancer but the exact mechanism is not understood. Similarly, histamine is a neurotransmitter and neuromodulator which regulate various functions such as inflammation, gastric acid secretion, memory, and learning. The inactivation of histamine is dependent on HNMT in mammalian brain. Histaminergic defects are involved in multiple neurodegenerative diseases, but the involvement of HNMT in disease progression is yet to be established. Hence, we have initiated medical chemistry campaigns to develop drug like selective inhibitors of GNMT and HNMT from the novel discovered hits. We believe these inhibitors will serve as valuable chemical biology tools to elucidate the role of these SMMTases in disease biology. In addition to the biochemical MTase-GloTM screening assay, HiBiT-tagged GNMT and HNMT NanoLuc® CETSA, and SPR, are being used to develop the structure activity relationships within these chemotypes; we will present our progress in these efforts.

Scientific Focus Area: Chemical Biology

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