Uses
STM2457 is a first-in-class, highly potent, selective and orally active METTL3 inhibitor with an IC50 of 16.9 nM. STM2457 can be used for the research of acute myeloid leukaemia (AML)[1][2].
Definition
ChEBI: STM2457 is a secondary carboxamide resulting from the formal condensation of the carboxy group of 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid with the primary amino group of 1-[2-(aminomethyl)imidazo[1,2-a]pyridin-6-yl]-N-(cyclohexylmethyl)methanamine. It is a highly potent and selective first-in-class small molecule inhibitor of METTL3 (N6-adenosine-methyltransferase 70 kDa subunit) enzyme activity and exhibits anti-leukaemic activity. It has a role as an EC 2.1.1.348 (mRNA m6A methyltransferase) inhibitor, an antineoplastic agent and an apoptosis inducer. It is an imidazopyridine, a secondary carboxamide, a secondary amino compound and a pyridopyrimidine.
Biological Activity
STM2457 is a potent and highly selective SAM-binding site METTL3 (MT-A70) m6A methyltransferase inhibitor (IC50 = 16.9 nM, Kd = 1.4 nM by SPR, using METTL3-METTL14 complex; no potency toward other RNA/DNA/protein methyltransferases or 486 kinases). STM2457 selectively inhibits human AML proliferation (IC50 = 0.6-10.3 μM) and the clonogenic potential of primary mouse AML, but not normal mouse haematopoietic stem/progenitor or human cord blood CD34+ cells. STM2457 impairs the expansion of AML patient-derived xenografts in mice in vivo (50 mg/kg i.p.) and significantly prolongs the animalμs lifespan. STM2457 is also reported to restrict β-coronavirus replication and spread.
References
[1] Wesley Peter Blackaby, et al. Mettl3 inhibitory compounds. WO2020201773A1.
[2] Eliza Yankova, et al. Small molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature. 2021 Apr 26. DOI:
10.1038/s41586-021-03536-w
