M5049 (Enpatoran)
M5049 | Unit size | Cat. code | Docs | Qty | Price |
---|---|---|---|---|---|
TLR7/TLR8 inhibitor - InvitroFit™ |
5 mg |
inh-m5049 |
Specific TLR7 and TLR8 dual inhibitor
Inhibition of TLR7 and TLR8 signaling by M5049
M5049 (also known as Enpatoran) is a small molecule that functions as a dual and selective inhibitor of TLR7 and TLR8 [1]. Its potency has been demonstrated in a range of in vitro assays and mouse lupus models in vivo [1]. M5049 efficiently inhibits human (h)TLR7, mouse (m)TLR7, and hTLR8, but not mTLR8, as assessed using InvivoGen's reporter cell lines HEK-Blue™ hTLR7, mTLR7, hTLR8, and mTLR8 (see Figure 1).
Mode of action:
Structural studies have revealed that M5049 binds and stabilizes the hTLR8 dimer in its resting (inactive) state, antagonizing the binding of any TLR8 ligands [1]. A similar mode of action has been suggested for TLR7 inhibition.
Importantly, M5049 blocks the activation of TLR7 and TLR8 without having any effect on other endosomal TLRs, i.e. TLR3 and TLR9 (see Figure 3).
Key features of M5049:
- M5049 specifically inhibits human TLR7, human TLR8, and mouse TLR7.
- M5049 acts as an antagonist that prevents the binding of TLR7 and TLR8 ligands to their receptors.
- InvitroFit™: each lot of M5049 is highly pure (≥95%) and functionally tested.
References:
1. Vlach J. et al., 2020. Discovery of M5049: a novel selective Toll-Like Receptor 7/8 inhibitor for treatment of autoimmunity. J Pharmacol Exp Ther. 376:397.
Back to the topSpecifications
CAS number: 2101938-42-3
Formula: C16H15F3N4
Molecular weight: 320.32 g/mol
Solubility: 62.4 mM (20 mg/ml) in H2O
Working concentration: 40 nM - 1 μM for cellular assays
Quality control:
- Purity: ≥95% (UHPLC)
- The inhibition of human TLR7, human TLR8, and mouse TLR7 by M5049 has been confirmed using cellular assays.
- The absence of bacterial contamination (e.g. lipoproteins and endotoxins) has been confirmed using HEK-Blue™ hTLR2 and HEK-Blue™ hTLR4 cells.
Contents
- 5 mg of lyophilized M5049
M5049 is shipped at room temperature.
Upon receipt, store M5049 at -20 °C. Upon resuspension of M5049 in H2O, prepare aliquots and store them at -20 °C.
The resuspended product is stable for 6 months when properly stored.
Avoid repeated freeze-thaw cycles.
Details
TLR7 and TLR8 are both activated by single-stranded (ss)RNA but also RNA molecules found in immune complexes with RNA protein-binding autoantibodies [1]. Thus, these two TLRs play a beneficial role in clearing microbial infections, but they can also contribute to the pathogenesis of autoimmune diseases such as cutaneous and systemic lupus erythematosus (CLE/SLE) [1-3]. In addition, it is postulated that TLR7/8 may play a role in the cytokine storm in severe coronavirus disease 2019 (COVID-19) pneumonia [2,3]. M5049 is currently under investigation as an oral treatment for lupus (NCT04647708) and severe COVID-19 (NCT04448756).
Chemical structure of M5049
References:
1. Vlach J. et al., 2020. Discovery of M5049: a novel selective Toll-Like Receptor 7/8 inhibitor for treatment of autoimmunity. J Pharmacol Exp Ther. 376:397.
2. Port A. et al., 2021. Phase 1 study in healthy participants of the safety, pharmacokinectics, and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll-like receptors 7 and 8. Pharmacol Res Perspect 9(5):e00842.
3. Klopp-Schulze I. et al. 2022. Applying Modeling and Simulations for Rational Dose Selection of Novel Toll-Like Receptor 7/8 Inhibitor Enpatoran for Indications of High Medical Need. Clin Pharmacol Ther, 112: 297-306.