Inhibition of METTL3-METTL14

STM2457 inhibits METTL3-METTL14 activity with IC50 of 16.9 nM.

Cell lines

Human AML cells, mouse AML cells, MOLM-13

Preparation method

The solubility of this compound in DMSO is > 1 mM.

Reaction Conditions

3 days

Applications

STM2457 shows its anti-leukaemic activity by the pharmacological inhibition of METTL3 on SP1 and BRD4.

Animal models

NSG mice (primary murine MLL-AF9/Flt3^ITD/+)

Dosage form

50 mg/kg, intraperitoneal injection, STM2457 was dissolved in 20% (w/v) 2-hydroxyprolpy β-cyclodextrin vehicle.

Applications

STM2457 decrease total m⁶A levels on poly-A⁺-enriched RNA of METTL3, reduces human CD45⁺cells in the bone marrow and spleen and impair engraftment and AML expansion in vivo at the dose of 50 mg/kg.

• EMBO Rep (2021): e52491.PMID:34747116

STM2457, an inhibitor of METTL3-METTL14 catalytic activity with IC₅₀of 16.9 nM, can directly bind to the METTL3-METTL14 with a high affinity (K_d) of 1.4 nM. STM2457, also shows greater than 1,000-fold selectivity for METTL3 compared to other RNA, DNA and protein methyltransferases.^[1]

STM2457 can inhibit the proliferation of human AML cells but not normal non-lekaemic haemopoietic cells. What’s more, STM2457 can reduce the clonogenic potential of primary mouse AML cells and inhibit METTL3 in MOLM-13 cells, which causes myeloid differentiation and cell cycle arrest.^[1]

STM2457 can impair engraftment and AML expansionin vivoand significantly prolong the mouse lifespan. It also reduces human CD45⁺cells in the bone marrow and spleen.^[1]

Reference:
[1] Yankova, E., Blackaby, W., Albertella, M. et al. Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature 593, 597–601 (2021).