Enpatoran is an Orally Active and Dual TLR7/8 Inhibitor

Toll-like receptors 7 and 8 (TLR7/8) are receptors for single-stranded RNA that reside in the endosome. TLR8 mainly expresses in neutrophils, monocytes, and myeloid dendritic cells. While TLR7 exists in B cells, monocytes, and plasmacytoid dendritic cells (pDCs).

TLR7 and 8 shares some common downstream signaling. What’s more, TLR7 activation is likely to stimulate the interferon regulatory factor (IRF) pathway, resulting in the production of type I interferon (IFN). While TLR8 activation results in nuclear factor-kappa B (NF-κB) activation for some inflammatory cytokines production.

Both small molecule agonists and larger RNA molecules are able to activate TLR7/8. And RNA molecules that exist in immune complexes with RNA protein-binding auto antibodies gain access to the endosome as they are taken up via B cell receptors or Fc receptors in autoimmunity. Inhibiting TLR7/8 requires compounds that can block ligands with varying structures from binding to the receptors.

Enpatoran is a potent and orally active dual TLR7/8 inhibitor. It is inactive against TLR3, TLR4, and TLR9.

Firstly, in vitro, this compound can block molecule synthetic ligands and natural endogenous RNA ligands. It inhibits the production of IL-6 stimulated by all the ligands (miR-122, Let7c RNA, Alu RNA, and R848). And the IC50 values are ranging from 35 to 45 nM.

In a pharmacokinetics analysis in CD1 mice, Wistar rats, and beagle dogs. Enpatoran exhibits high oral bioavailabilities (mouse 100%, rat 87%, dog 84%) following oral administration. Following intravenous administration, Enpatoran exhibits moderate half-lives (mouse 1.4, rat 5.0, and dog 13 h) due to high plasma clearance (1.4, 1.2, and 0.59 L/h/kg, respectively). Besides, the large volumes of distribution are 2.7, 8.7, and 5.7 L/kg for mouse, rat, and dog, respectively.
In C57BL/6 mice, Enpatoran inhibits cytokines release in vivo. The TLR7/8 agonist R848 stimulates both IFN-α and IL-6 production in mice. However,pre-treatment with Enpatoran before R848 dose-dependently inhibits the production of IL-6 and IFN-α.

In conclusion, Enpatoran can block both innate and adaptive autoimmunity. It has the potential for immune disease research.


[1] Jaromir Vlach, et al. J Pharmacol Exp Ther. 2020 Dec 16; JPET-AR-2020-000275.