Stm2457
[CAS# 2499663-01-1]

Identification

• Classification: Biochemical >> Inhibitor >> Epigenetics
• Name: Stm2457
• Synonyms: N-[[6-[(cyclohexylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxopyrido[1,2-a]pyrimidine-2-carboxamide
• Molecular Formula: C₂₅H₂₈N₆O₂
• Molecular Weight: 444.53
• CAS Registry Number: 2499663-01-1
• SMILES: C1CCC(CC1)CNCC2=CN3C=C(N=C3C=C2)CNC(=O)C4=CC(=O)N5C=CC=CC5=N4

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Index of refraction: 1.703 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P261-P280-P301+P312-P302+P352-P305+P351+P338

Discovory and Applicatios

STM2457 is a small-molecule inhibitor that selectively targets methyltransferase-like 3 (METTL3), an enzyme responsible for catalyzing N6-methyladenosine (m\&sup6;A) modifications on RNA. The discovery of STM2457 marked a significant advance in the study of RNA epigenetics, as it was the first potent and selective catalytic inhibitor developed to directly inhibit METTL3 activity. The development of STM2457 was driven by growing evidence that METTL3-mediated m\&sup6;A modifications play a critical role in regulating RNA metabolism, stability, and translation, and that dysregulation of this enzyme is implicated in various cancers and other diseases.

The identification of STM2457 arose from a focused drug discovery program seeking compounds capable of binding to the S-adenosylmethionine (SAM) binding pocket of METTL3. By competitively inhibiting SAM, STM2457 effectively blocks the methyltransferase activity of the METTL3-METTL14 complex. This binding specificity allows STM2457 to reduce global m\&sup6;A levels on RNA in cells without broadly affecting other RNA methyltransferases. The compound demonstrates high potency with an inhibitory concentration in the low nanomolar range and shows no significant off-target activity against related enzymes.

STM2457’s discovery provided a valuable chemical tool to probe the biological functions of METTL3 in both normal and pathological contexts. Preclinical studies revealed that STM2457 potently decreases m\&sup6;A RNA modification levels in treated cells, leading to altered RNA stability and gene expression profiles. In cancer research, STM2457 showed remarkable effects in models of acute myeloid leukemia (AML), where METTL3 is frequently overexpressed and contributes to leukemogenesis. Treatment with STM2457 impaired leukemia stem cell self-renewal and proliferation, resulting in suppressed tumor growth and prolonged survival in animal models. This inhibitory effect on METTL3 also modulated critical oncogenic pathways, indicating the therapeutic potential of targeting RNA methylation in AML.

Beyond AML, STM2457 has been investigated in other cancers where METTL3 plays a role in tumor progression. Studies in prostate cancer models demonstrated that STM2457 could enhance the efficacy of DNA damage response-targeting agents, such as PARP inhibitors. The combination led to increased apoptosis and DNA damage, suggesting a synergistic effect that may improve treatment outcomes in solid tumors. These findings have opened avenues for exploring STM2457 as part of combination therapies to overcome drug resistance and enhance cancer cell killing.

STM2457’s pharmacokinetic properties support its use in in vivo studies, exhibiting oral bioavailability and favorable metabolic stability. This enables convenient dosing regimens in animal models and facilitates translation to clinical research. The compound’s safety profile in preclinical evaluations indicated tolerability at therapeutic doses, though further studies are required to assess long-term effects and potential toxicities.

The applications of STM2457 extend beyond oncology, as METTL3-mediated m\&sup6;A modification is involved in various biological processes including immune regulation, stem cell maintenance, and viral replication. The availability of STM2457 has allowed researchers to dissect these pathways with precision and has spurred interest in developing METTL3 inhibitors as therapeutic agents in diverse diseases.

Overall, STM2457 represents a pioneering chemical inhibitor in the field of RNA epigenetics. Its selective inhibition of METTL3 offers a novel approach to modulate gene expression at the RNA level and presents promising therapeutic implications, especially in cancers with aberrant METTL3 activity. Ongoing research continues to elucidate the full spectrum of STM2457’s biological effects and its potential utility as a component of future treatment strategies.

References

2021. Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature, 593(7860).
DOI: 10.1038/s41586-021-03536-w

2022. Roles and drug development of METTL3 (methyltransferase-like 3) in anti-tumor therapy. European Journal of Medicinal Chemistry, 230.
DOI: 10.1016/j.ejmech.2022.114118