molecules of the month

The Storm Therapeutics/Cambridge METTL3 RNA methyltransferase inhibitor, STM-2457, is a first-in-class catalytic inhibitor of the METTL3 RNA modifying enzyme. DNA-methyltransferase and other epigenetic targets such as HDACs have been explored for their potential roles in cancer and other diseases, and this compound brings RNA modifying enzymes into the druggable target space. The compound is highly specific for METTL3, with no inhibition of other RNA, DNA, or protein methyltransferases, despite being competitive with the ubiquitous SAM-cofactor. Human cellular target engagement was demonstrated with a thermal-shift experiment, and an X-ray co-crystal structure helps explain the selectivity observed. While the compound demonstrates activity in patient-derived xenografts (PDX) and on leukaemic stem cell populations, no significant effects were observed in normal hematopoietic stem cells (HSCs).…