BMS-986256
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Cat.code:
inh-afi
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ABOUT
Specific TLR7 and TLR8 dual inhibitor
BMS-986256 (Afimetoran) is an indole-based small molecule that functions as a dual and selective inhibitor of TLR7 and TLR8 [1, 2]. Its potency has been demonstrated in various in vitro assays and a mouse lupus model in vivo [1, 2]. BMS-986256 is currently under phase II clinical investigation in patients with systemic lupus erythematosus (SLE) [3, 4].
BMS-986256 efficiently inhibits human (h)TLR7, mouse (m)TLR7, and hTLR8, but not mTLR8, as assessed using InvivoGen's HEK-Blue™ reporter cell lines overexpressing hTLR7, mTLR7, hTLR8, and mTLR8 (see figures).
BMS-986256 exerts inhibitory actions on both NF-κB and IRF pathways downstream hTLR7 and hTLR8, as assessed with THP1-Dual™-derived cells (see figures).
Importantly, BMS-986256 blocks the activation of TLR7 and TLR8 with no effect on other endosomal TLRs, i.e. TLR3 and TLR9 (see figures).
Mode of action
The specific binding mechanism of BMS-986256 is not known yet. However, it is hypothesized to behave similarly to other TLR7/8 antagonists by maintaining the inactive conformation of TLR7 and TLR8 receptors [2, 5]. Future research is needed to elucidate the exact mode of action of BMS-986256.
Key features of BMS-986256
- Indole-based small molecule
- Dual and selective inhibitor of TLR7- and TLR8-mediated NF-κB and IRF pathways
- Potent inhibitor of human TLR7, human TLR8, and mouse TLR7
- No action on mouse TLR8 overexpressed in HEK-Blue™ cells
- InvitroFit™: each lot of BMS-986256 is highly pure (≥95%) and functionally tested.
References:
1. Bristol-Myers Squibb company. 04.01.2018. WO 2018/005586 A1. [1,2,4] Triazolo [1,5-A] Pyridinyl substituted indole compounds.
2. Zheng H. et al., 2023. Recent Advances on Small-Molecule Antagonists Targeting TLR7. Molecules 28 (2), pp.634. ff10.3390/molecules28020634ff. ffhal-04564284.
3. Kalliokas. et al., 2021. Targeting TLR Signaling Cascades in Systemic Lupus Erythematosus and Rheumatoid Arthritis: An Update. Biomedicines 12(1):138.
4. NCT04895696. www.clinicaltrials.gov. As accessed in October 2024.
5. 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.
All products are for research use only, and not for human or veterinary use.
InvitroFit™
InvitroFit™ is a high-quality standard specifically adapted for in vitro studies of inhibitors. InvitroFit™ products are highly pure (≥95%) and guaranteed free of bacterial contamination, as confirmed using HEK Blue™ TLR2 and HEK Blue™ TLR4 cellular assays. Each lot is rigorously tested for functional activity using validated (or proprietary) cellular models. This grade ensures reliability and reproducibility for your research applications.
SPECIFICATIONS
Specifications
TLR7, TLR8
Human (TLR7/TLR8), Mouse (TLR7)
C26H32N6O
11.25 mM (5 mg/ml) in DMSO
in vitro: 2 nM - 1 μM (see figures), in vivo: 0.25 mg/kg - 2.5 mg/kg [4]
Negative (tested using EndotoxDetect™ assay)
In vitro cellular assays
Each lot is functionally tested and validated using cellular assays.
CONTENTS
Contents
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Product:BMS-986256
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Cat code:inh-afi
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Quantity:2 mg
Shipping & Storage
- Shipping method: Room temperature
- -20 °C
- Avoid repeated freeze-thaw cycles
Storage:
Caution:
Details
TLR7 and TLR8 are both activated by single-stranded (ss)RNA and 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].
BMS986256 is described as an equipotent dual TLR7/TLR8 inhibitor using in vitro cellular assays [4]. However, in-house data suggest that the in vitro potency for each inhibitor depends on the choice of TLR7/TLR8-expressing cell lines and the type of agonists.
BMS986256 is currently under investigation as an oral treatment for SLE [5]. Interestingly, BMS-986256 demonstrates steroid-sparing effects in a mouse lupus model, a key feature that could help overcome glucocorticoid resistance and side effects in SLE patients [6].
Chemical structure of BMS-986256
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.
4. Bristol-Myers Squibb company. 04.01.2018. WO 2018/005586 A1. [1,2,4] Triazolo [1,5-A] Pyridinyl substituted indole compounds
5. NCT04895696. www.clinicaltrials.gov. As accessed in October 2024.
6. Dudhgaonkar S, et al., 2023. AB0132 Afimetoran (BMS-986256), an equipotent TLR7/8 antagonist, demonstrates steroid-sparing effects in a lupus mouse model. Annals of the Rheumatic Diseases 82:1245-1246.
DOCUMENTS
Documents
Technical Data Sheet
Validation Data Sheet
Safety Data Sheet
Certificate of analysis
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