TAK-715 is a potent, selective, and orally active p38 mitogen-activated protein kinase (p38 MAPK) inhibitor, with IC50 values of 7.1nM and 200nM for p38α and p38β, respectively[1]. The p38 MAPK pathway is a key regulator of pro-inflammatory cytokine biosynthesis at both transcriptional and translational levels and plays a critical role in the initiation and progression of inflammation[2]. TAK-715 is commonly used in the treatment and research of inflammatory diseases such as rheumatoid arthritis, as well as diseases related to lipid accumulation and tissue degeneration[1,3].
In vitro, pretreatment of rat nucleus pulposus cells (NPCs) with TAK-715 (0.5-1μM) for 2h followed by co-treatment with IL-1β for 48h significantly reduced the expression of pro-inflammatory factors COX-2 and HMGB1, suppressed the expression of apoptosis-related proteins Bax and cleaved-caspase 3, and up-regulated the anti-apoptotic protein Bcl-2[4]. Treatment of 3T3-L1 preadipocytes with TAK-715 (10μM) for 8 days significantly suppressed lipid droplet accumulation and intracellular triglyceride content without cytotoxicity[5]. Treatment of melanoma A375 cell line with TAK-715 (25μM) for 24h reduced cell viability in a dose-dependent manner[6].
In vivo, pretreatment of BALB/c mice in a transfusion-related acute lung injury (TRALI) model with TAK-715 (10mg/kg; i.p.) 1h before injection of an MHC-I monoclonal antibody (mAb) effectively reduced MAPK phosphorylation and TLR3 expression, and significantly inhibited the levels of multiple inflammatory cytokines and mast cell activation[7]. Intradiscal injection of TAK-715 (1μM; 5μL) into an SD rat model of disc degeneration induced by caudal vertebral puncture improved magnetic resonance imaging (MRI) signal intensity after 8 weeks and exerted beneficial effects on the tissue of the inner nucleus pulposus[4].
References:
[1] MIWATASHI S, ARIKAWA Y, KOTANI E, et al. Novel inhibitor of p38 MAP kinase as an anti-TNF-α drug: discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1, 3-thiazol-5-yl]-2-pyridyl] benzamide (TAK-715) as a potent and orally active anti-rheumatoid arthritis agent[J]. Journal of Medicinal Chemistry, 2005, 48(19): 5966-5979.
[2] SAKLATVALA J. The p38 MAP kinase pathway as a therapeutic target in inflammatory disease[J]. Current Opinion in Pharmacology, 2004, 4(4): 372-377.
[3] LI L, ZHANG G, YANG Z, et al. Stress-activated protein kinases in intervertebral disc degeneration: unraveling the impact of JNK and p38 MAPK[J]. Biomolecules, 2024, 14(4): 393.
[4] WANG K, YAO D, LI Y, et al. TAK-715 alleviated IL-1β-induced apoptosis and ECM degradation in nucleus pulposus cells and attenuated intervertebral disc degeneration ex vivo and in vivo[J]. Arthritis Research & Therapy, 2023, 25(1): 45.
[5] PERUMAL N L, MUFIDA A, YADAV A K, et al. Suppression of lipid accumulation in the differentiation of 3T3-L1 preadipocytes and human adipose stem cells into adipocytes by TAK-715, a specific inhibitor of p38 MAPK[J]. Life, 2023, 13(2): 412.
[6] XIE Y, WANG R, XU M, et al. Potential of CLSPN as a therapeutic target in melanoma: a key player in melanoma progression and tumor microenvironment[J/OL]. Journal of Translational Medicine, 2025, 23(1): 470.
[7] FANG X, SONG T, ZHENG L, et al. Targeting mast cell activation alleviates anti-MHC I antibody and LPS-induced TRALI in mice by pharmacologically blocking the TLR3 and MAPK pathway[J]. Biomedicine & Pharmacotherapy, 2024, 180: 117456.
TAK-715是一种高效，具有选择性和口服活性的p38 丝裂原活化蛋白激酶（p38 MAPK）抑制剂，对p38α和p38β的IC50值分别为7.1nM和200nM[1]。p38 MAPK通路是在转录和翻译阶段促炎细胞因子生物合成的关键调节因子，在炎症的发生和发展中起重要作用[2]。TAK-715通常用于炎症性疾病如类风湿性关节炎、以及与脂质积累和组织退变相关疾病的治疗和研究[1,3]。
在体外，TAK-715（0.5-1μM）与大鼠髓核细胞（NPCs）预孵育2h，随后与IL-1β共处理48h，显著降低了促炎因子COX-2和HMGB1的表达，并抑制了细胞凋亡相关蛋白Bax和cleaved-caspase 3的表达，同时上调了抗凋亡蛋白Bcl-2[4]。TAK-715（10μM）处理3T3-L1前脂肪细胞8天，显著抑制了脂滴积累和细胞内甘油三酯含量，且无细胞毒性[5]。TAK-715（25μM）处理黑色素瘤A375细胞系24h，以剂量依赖性方式降低了细胞活力[6]。
在体内，TAK-715（10mg/kg; i.p.）在注射MHC-I单克隆抗体（mAb）前1h预处理输血相关急性肺损伤（TRALI）模型BALB/c小鼠，可有效降低MAPK磷酸化和TLR3表达，并显著抑制多种炎症细胞因子的水平和肥大细胞的活化[7]。TAK-715（1μM; 5μL）通过椎间盘内注射到SD大鼠尾椎穿刺诱导的椎间盘退变模型中，8周后改善了核磁共振成像（MRI）的信号强度，并对内侧髓核中的组织有益[4]。