L48H37, a Specific Myeloid Differentiation Protein 2 (MD2) Inhibitor

By Edward Jenner 2020-08-11 #Curcumin, #IL-6, #LPS-TLR4/MD2, #Sepsis, #TNF-α

Many immune diseases may result in the excessive production of various inflammatory cytokines as well as cellular injury. Curcumin plays an important role as an anti-inflammatory agent. Due to Curcumin’s poor stability under physiological conditions, a series of mono-carbonyl curcumin analogs without the β-diketone moiety of curcumin appears.

L48H37 is an analog of Curcumin with improved chemical stability.

L48H37 is a potent and specific myeloid differentiation protein 2 (MD2) inhibitor. And this smallscale inhibits the interaction and signaling transduction of LPS-TLR4/MD2.

L48H37 has anti-inflammatory effects in vitro. In mouse macrophages, it inhibits LPS-induced inflammation, particularly TNF-α and IL-6 production and gene expression. This compound also has anti-cancer effects. In A549 and H460 cells, L48H37decreases the viability with IC₅₀ values of 5.3 µM and 2.3 µM, respectively. As an analog of Curcumin, it is more effective in lung cancer cells. Whatmore shows low cytotoxicity on normal human lung epithelial cells (BEAS-2B) with IC₅₀ of 21 μM.

L48H37 induces cell apoptosis and cell arrest. It dose‐dependently inhibited the expression of p‐Cdc2 and Cdc2 and increases the expression of p53. At the same time, L48H37 also shows increased levels of cleaved poly (ADP‐ribosyl) polymerase (PARP) and reduced levels of anti‐apoptotic protein Bcl‐2 in H460 and A549 cells. When L48H37 is at 4 µM, it rapidly induces intracellular ROS levels dose-dependently in H460 and A549 cells.

In the H460 xenograft tumor mouse model, L48H37 inhibits H460 xenograft tumor growth and exhibits anti-tumor activity. It reduces tumor wet weights when it compares to the vehicle control. At the same time, L48H37 decreased the levels of p‐STAT3 and increased the levels of p‐EIF2α and ATF4 in extracted-tissues. Furthermore, it has less toxicity in vivo without significant structural changes in mice.

In conclusion, L48H37, as a novel MD2 inhibitor which can directly bind to MD2. It blocks the LPS-TLR4/MD2 signaling activation and suppresses the expression of inflammatory cytokine in vitro and in vivo.

Reference:

Panagiota Zania, et al. J Pharmacol Exp Ther. 2006 Jul;318(1):246-54.