MyD88-IN-3

MyD88-IN-3 is an orally active, selective MyD88 Inhibitor. MyD88-IN-3 specifically targets the TIR domain of MyD88 ( K D = 28.5 μM), thereby preventing MyD88 self-polymerization and interaction with TLRs, which suppresses the activation of MAPK and NF-κB pathways. MyD88-IN-3 demonstrates significant anti-inflammatory efficacy and effectively mitigates Acute Lung Injury (ALI) symptoms in CLP (cecal ligation and puncture) and Lipopolysaccharides (LPS)-induced ALI models. MyD88-IN-3 can be used for the study of ALI ^[1].

In Vivo, MyD88-IN-3 (500 mg/kg, 1000 mg/kg, oral gavage, once daily for 10 days) exhibits advantageous in vivo safety in SD rats^[1]. MyD88-IN-3 (20 mg/kg, Oral gavage, pretreated 6 h) mitigates sepsis-induced ALI in C57BL/6 mice^[1]. MyD88-IN-3 (20 mg/kg, Oral gavage, pretreated 30 min) Attenuated LPS-Induced ALI in C57BL/6 mice^[1].

In Vitro, MyD88-IN-3 (Compound 3g) (1.1-30 μM) demonstrates potent anti-inflammatory effects by significantly inhibiting IL-6 secretion in the mouse macrophage J774A.1 (IC₅₀ = 1.32 μM) and human THP-1 (IC₅₀ = 0.75 μM ) macrophages differentiated with PMA^[1]. MyD88-IN-3 (10 μM, pretreatment for 2 h, followed by co-treatment with 0.5 μg/mL LPS for 30 minutes) restores the decreased expression level of IκBα induced by LPS, significantly reduces the phosphorylation of p38, inhibits the phosphorylation of JNK, suppresses phosphorylation and nuclear translocation of p65, and inhibits LPS-induced activation of the MAPK pathway, leading to nuclear translocation of c-Jun in J774A.1 macrophage^[1]. MyD88-IN-3 (5 μM, 10 μM) can inhibit MyD88 homodimerization in J774A.1^[1]. MyD88-IN-3 (10 μM, 2 h) can inhibit the interaction between MyD88 and TLR4 in J774A.1^[1]. MyD88-IN-3 (10 μM, 4 h) improves the thermal stability of MyD88, preserving roughly 50% of MyD88 at 64 °C^[1]. MyD88-IN-3 binds efficiently to the TIR domain (KD = 28.5 μM), while exhibiting no binding affinity for the DD domain (KD = 1.32 M)^[1].

References:
[1]. Chen P, et al. Discovery of MyD88-IN-3 as an Orally Bioavailable, TIR Domain Selective, and Potent MyD88 Inhibitor for the Treatment of Acute Lung Injury. J Med Chem. 2025 Sep 25;68(18):19626-19644.