T6167923 is a highly selective inhibitor of the myeloid differentiation factor 88 (MyD88)-dependent signaling pathway[1]. T6167923 specifically binds to the TIR domain of MyD88, directly inhibiting its homodimer formation and subsequently suppressing MyD88-dependent inflammatory signaling[1, 2]. T6167923 is commonly used in the treatment and research of toxic shock and other MyD88-related inflammatory diseases[3, 4].
In vitro, pre-incubation of peripheral blood mononuclear cells (PBMCs) with T6167923 (2-10μM) for 30min, followed by stimulation with 200ng/mL Staphylococcal enterotoxin B (SEB) for 16h, effectively inhibited SEB-induced production of pro-inflammatory cytokines TNF-α, IFN-γ, IL-6, and IL-1β, with IC50 values ranging from 2 to 10μM[1]. Co-incubation of human immortalized keratinocyte HaCaT cells with T6167923 (3μM) and 1μg/mL lipopolysaccharide (LPS) for 36h significantly promoted cell migration and accelerated wound healing[5]. Treatment of BV2 cells with T6167923 (2μM) for 24h significantly reduced the heme-induced expression of the M1 microglial surface marker CD86[6]. Pre-treatment of mouse peritoneal macrophages with T6167923 (5, 10, 20μM) for 1h, followed by infection with Pseudorabies virus (PRV) for 24h, significantly suppressed PRV-induced mRNA and protein levels of pro-IL-1β[7].
In vivo, intraperitoneal administration of T6167923 (0.17mg/mouse or 1mg/mouse) to BALB/c mice 30min before SEB challenge provided dose-dependent protection against lethal toxic shock induced by a combined challenge of SEB (1μg) and LPS (90μg). The 0.17mg dose group achieved a 50% survival rate, while the 1mg dose group achieved 100% survival[1]. Subcutaneous injection of T6167923 (10mM; 400μL; once daily) for 5 days into the wound area of LPS-treated Balb/c mice accelerated wound healing, reduced stratum corneum thickness, and resulted in thinner and more orderly arranged dermal collagen[5].
References:
[1] OLSON M A, LEE M S, KISSNER T L, et al. Discovery of small molecule inhibitors of MyD88-dependent signaling pathways using a computational screen[J]. Scientific Reports, 2015, 5: 14246.
[2] SAQIB U, BAIG M S. Identifying the inhibition of TIR proteins involved in TLR signalling as an anti-inflammatory strategy[J]. SAR and QSAR in Environmental Research, 2018, 29(4): 295-318.
[3] SAIKH K U. MyD88 and beyond: a perspective on MyD88-targeted therapeutic approach for modulation of host immunity[J]. Immunologic Research, 2021, 69(2): 117-128.
[4] DI PADOVA F, QUESNIAUX V F, RYFFEL B. MyD88 as a therapeutic target for inflammatory lung diseases[J]. Expert Opinion on Therapeutic Targets, 2018, 22(5): 401-408.
[5] XU Z, CHENG C, ZHANG Y, et al. Lipopolysaccharide induces skin scarring through the TLR4/MyD88 inflammatory signaling pathway in dermal fibroblasts[J]. Burns, 2023, 49(8): 1997-2006.
[6] WEI X, ZHANG F, CHENG D, et al. Free heme induces neuroinflammation and cognitive impairment by microglial activation via the TLR4/MyD88/NF-κB signaling pathway[J]. Cell Communication and Signaling, 2024, 22: 16.
[7] ZHOU Q, ZHANG L, LIN Q, et al. Pseudorabies virus infection activates the TLR-NF-κB axis and AIM2 inflammasome to enhance inflammatory responses in mice[J]. Journal of Virology, 2023, 97(3): e00003-23.