An inhibitor of the METTL3/14 complex
STM2457, an inhibitor of METTL3-METTL14 catalytic activity with IC50 of 16.9 nM, can directly bind to the METTL3-METTL14 with a high affinity (Kd) 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 expansion in vivo and significantly prolong the mouse lifespan. It also reduces human CD45+cells in the bone marrow and spleen. [1]
STM2457是METTL3-METTL14催化活性的抑制剂，其IC50为16.9nM，可以以1.4nM的高亲和力（Kd）直接结合METTL3-METTL14。STM2457与其他RNA、DNA和蛋白质甲基转移酶相比，对METTL3也显示出大于1000倍的选择性。[1]
STM2457可以抑制人AML细胞的增殖，但不能抑制正常非白血病造血细胞的增殖。此外，STM2457可以降低原代小鼠AML细胞的克隆潜能，并抑制MOLM-13细胞中的METTL3，从而导致骨髓分化和细胞周期停滞。[1]
STM2457可在体内损害植入和AML扩增，并显著延长小鼠寿命。它还减少了骨髓和脾脏中的人类CD45+细胞。[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).
| Kinase experiment [1]: | |
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Inhibition of METTL3-METTL14 |
STM2457 inhibits METTL3-METTL14 activity with IC50 of 16.9 nM. |
| Cell experiment [1]: | |
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Cell lines |
Human AML cells, mouse AML cells, MOLM-13 |
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Preparation method |
The solubility of this compound in DMSO is > 1 mM. |
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Reaction Conditions |
3 days |
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Applications |
STM2457 shows its anti-leukaemic activity by the pharmacological inhibition of METTL3 on SP1 and BRD4. |
| Animal experiment [1]: | |
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Animal models |
NSG mice (primary murine MLL-AF9/Flt3ITD/+) |
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Dosage form |
50 mg/kg, intraperitoneal injection, STM2457 was dissolved in 20% (w/v) 2-hydroxyprolpy β-cyclodextrin vehicle. |
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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. |
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参考文献: [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). |
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