TJ-M2010-5

TJ-M2010-5 is a MyD88 inhibitor that acts by binding to the Toll/Interleukin-1 receptor (TIR) domain of myeloid differentiation factor 88 (MyD88), interfering with its homodimerization and the TLR/MyD88 signaling pathway^[1]. MyD88 is a key adaptor protein in innate immune signaling, serving as a bridge connecting upstream TLRs/IL-1R and downstream NF-κB pathway signal transduction, and is involved in important physiological processes such as cell regeneration, dedifferentiation, phenotypic transformation, cell necrosis, and inflammatory responses^[2]. TJ-M2010-5 is commonly used in research related to MyD88-associated signaling pathways and conditions such as myocardial ischemia/reperfusion injury^[3,4].

In vitro, pretreatment of mouse bone marrow-derived macrophages with TJ-M2010-5 (10, 30μM) for 2h, followed by stimulation with lipopolysaccharide (LPS; 500ng/mL) for 6h and subsequent treatment with ATP (5mM) for 2h, resulted in reduced Gasdermin-D (GSDMD) cleavage and decreased cell mortality, significantly inhibiting LPS and ATP-induced pyroptosis^[5]. Pretreatment of BV-2 cells with TJ-M2010-5 (10, 20μM) for 2h, followed by stimulation with LPS (1μg/mL) for 24h, effectively inhibited LPS-induced morphological activation of BV-2 cells and reduced the secretion levels of TNF-α and IL-6 in the cell supernatant^[6]. Co-treatment of LX-2 cells with TJ-M2010-5 (10-30μM) and transforming growth factor-β1 (TGF-β1) for 36h dose-dependently inhibited the proliferation of LX-2 cells^[7].

In vivo, prophylactic administration of TJ-M2010-5 (50mg/kg/day) via intraperitoneal injection to BALB/c mice for 3 consecutive days lowered serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH), and reduced liver histopathological damage scores, significantly improving liver function and alleviating liver injury in a mouse model of hepatic ischemia-reperfusion^[5]. Administration of TJ-M2010-5 (20mg/kg; i.p.) immediately after reperfusion in a mouse model of transient middle cerebral artery occlusion (tMCAO) significantly reduced cerebral infarction volume and improved neurological function scores after 24h^[8].

References:
[1] XIE L, JIANG F C, ZHANG L M, et al. Targeting of MyD88 homodimerization by novel synthetic inhibitor TJ-M2010-5 in preventing colitis-associated colorectal cancer[J]. Journal of the National Cancer Institute, 2016, 108(4): djv364.
[2] JANSSENS S, BEYAERT R. A universal role for MyD88 in TLR/IL-1R-mediated signaling[J]. Trends in Biochemical Sciences, 2002, 27(9): 474-482.
[3] MIAO Y, DING Z, ZOU Z, et al. Inhibition of MyD88 by a novel inhibitor reverses two-thirds of the infarct area in myocardial ischemia and reperfusion injury[J]. American Journal of Translational Research, 2020, 12(9): 5151.
[4] WANG L, HU D, XIE B, et al. Blockade of Myd88 signaling by a novel MyD88 inhibitor prevents colitis-associated colorectal cancer development by impairing myeloid-derived suppressor cells[J]. Investigational New Drugs, 2022, 40(3): 506-518.
[5] ZOU Z, SHANG R, ZHOU L, et al. The novel MyD88 inhibitor TJ-M2010-5 protects against hepatic ischemia-reperfusion injury by suppressing pyroptosis in mice[J]. Transplantation, 2023, 107(2): 392-404.
[6] LI Z, ZHAO M, ZHANG X, et al. TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway[J]. Frontiers in Pharmacology, 2022, 13: 1080438.
[7] XIE Y, DU D, ZHANG L, et al. TJ-M2010-5, a self-developed MyD88 inhibitor, attenuates liver fibrosis by inhibiting the NF-κB pathway[J]. Chemico-Biological Interactions, 2022, 354: 109839.
[8] JIANG F, XU C, FAN X H, et al. MyD88 inhibition attenuates cerebral ischemia-reperfusion injury by regulating the inflammatory response and reducing blood-brain barrier damage[J]. Neuroscience, 2024, 549: 121-137.

TJ-M2010-5是一种通过与髓样分化因子88（MyD88）的TIR结构域结合，干扰其同源二聚化及TLR/MyD88信号通路的MyD88抑制剂^[1]。MyD88是固有免疫信号传导中的关键转接蛋白，是上游TLRs/IL-1R 和下游NF-κB通路信号转导的桥梁，参与细胞再生、去分化、表型转化及细胞坏死和炎症反应等重要生理过程^[2]。TJ-M2010-5通常用于MyD88相关信号通路及心肌缺血/再灌注损伤等的研究^[3,4]。

在体外，TJ-M2010-5（10, 30μM）预处理小鼠骨髓来源巨噬细胞2h，随后使用脂多糖LPS（500ng/mL）刺激6h，再加入ATP（5mM）处理2h，导致Gasdermin-D（GSDMD）切割减少和细胞死亡率下降，显著抑制了由LPS和ATP诱导的细胞焦亡^[5]。TJ-M2010-5（10, 20μM）预处理BV-2细胞2h，随后加入LPS（1μg/mL）刺激24h，有效抑制了LPS诱导的BV-2细胞形态活化，并降低了细胞上清液中TNF-α和IL-6的分泌水平^[6]。TJ-M2010-5（10-30μM）与‌转化生长因子-β1（TGF-β1）共同处理LX-2细胞36h，能剂量依赖性地抑制LX-2细胞的增殖^[7]。

在体内，TJ-M2010-5（50mg/kg/day）通过腹腔注射预防性给药BALB/c小鼠连续3天，使血清中丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）和乳酸脱氢酶（LDH）的水平降低和肝组织病理损伤评分下降，显著改善了肝功能并减轻了小鼠肝缺血再灌注模型中的肝损伤^[5]。TJ-M2010-5（20mg/kg; i.p.）在灌注后立即给药短暂性脑中动脉闭塞（tMCAO）模型小鼠，24h后显著减小了脑梗死体积，并改善了神经功能评分^[8]。