GW441756 is a potent inhibitor of tropomyosin receptor kinase A (TrkA) with an IC₅₀ of 2nM, and GW441756 also exhibits inhibitory activity against leucine-rich repeat kinase 2 (LRRK2) with an IC₅₀ of 2.2µM[1-2]. By inhibiting the TrkA receptor, GW441756 blocks the nerve growth factor (NGF) signaling pathway, thereby affecting cell proliferation, differentiation, and apoptosis, and can increase caspase-3 levels to induce apoptosis. GW441756 can be used in cancer research and neurobiology studies[3-4].
In vitro, RD-ES and SK-ES-1 Ewing's sarcoma cells were treated with GW441756 (0-15µM) for 72 hours. GW441756 significantly inhibited cell proliferation. When used in combination with the TrkB-selective inhibitor Ana-12, GW441756 produced a more robust anti-proliferative effect than either inhibitor alone[5]. PC12 cells were pretreated with GW441756 (1µM) for 4 hours, followed by stimulation with nerve growth factor (NGF; 50ng/mL) for 24 hours. GW441756 completely inhibited NGF-induced neurite outgrowth and blocked the enhancing effect of Rivastigmine on neurite growth[6].
In vivo, in a CLP-induced sepsis model, mice received intraperitoneal injections of GW441756 (10mg/kg/day) for 22 days, starting 2 days before surgery. GW441756 completely abolished the protective effects of amitriptyline against neuronal loss, gliosis, cognitive dysfunction, and oxidative stress, and blocked amitriptyline's regulation of the Akt/GSK3β signaling pathway and caspase-3 expression[7]. In a rat model of chronic post-surgical pain induced by skin/muscle incision and retraction (SMIR), GW441756 (1-100µM; 10µl) was administered intrathecally once daily from day 10 to day 14 after surgery. GW441756 significantly alleviated mechanical allodynia and suppressed the upregulation of Nav1.7, SGK1, and p-Nedd4-2 proteins in the dorsal root ganglion[8].
References:
[1] Zhao F, Zou X, Li S, et al. BmK NSPK, a Potent Potassium Channel Inhibitor from Scorpion Buthus martensii Karsch, Promotes Neurite Outgrowth via NGF/TrkA Signaling Pathway. Toxins (Basel). 2021 Jan 5;13(1):33.
[2] Wood ER, Kuyper L, Petrov KG, et al. Discovery and in vitro evaluation of potent TrkA kinase inhibitors: oxindole and aza-oxindoles. Bioorg Med Chem Lett. 2004 Feb 23;14(4):953-7.
[3] Iimura A, Nishida E, Kusakabe M. Role of TrkA signaling during tadpole tail regeneration and early embryonic development in Xenopus laevis. Genes Cells. 2020 Feb;25(2):86-99.
[4] Zhang J, Liu H, Zhang W, et al. Identification of lncRNA-mRNA Regulatory Module to Explore the Pathogenesis and Prognosis of Melanoma. Front Cell Dev Biol. 2020 Dec 17;8:615671.
[5] Heinen TE, Dos Santos RP, da Rocha A, et al. Trk inhibition reduces cell proliferation and potentiates the effects of chemotherapeutic agents in Ewing sarcoma. Oncotarget. 2016 Jun 7;7(23):34860-80.
[6] Terada K, Migita K, Matsushima Y, et al. Cholinesterase inhibitor rivastigmine enhances nerve growth factor-induced neurite outgrowth in PC12 cells via sigma-1 and sigma-2 receptors. PLoS One. 2018 Dec 17;13(12):e0209250.
[7] Zhang L, Peng X, Ai Y, et al. Amitriptyline Reduces Sepsis-Induced Brain Damage Through TrkA Signaling Pathway. J Mol Neurosci. 2020 Dec;70(12):2049-2057.
[8] Liu BW, Zhang J, Hong YS, et al. NGF-Induced Nav1.7 Upregulation Contributes to Chronic Post-surgical Pain by Activating SGK1-Dependent Nedd4-2 Phosphorylation. Mol Neurobiol. 2021 Mar;58(3):964-982.
GW441756是一种原肌球蛋白受体激酶A（TrkA；IC50=2nM）抑制剂，同时对LRRK2（IC50=2.2μM）也有抑制作用[1-2]。GW441756通过抑制TrkA受体来阻断神经生长因子（NGF）信号通路，从而影响细胞增殖、分化和凋亡，并可增加caspase-3并诱导细胞凋亡。GW441756可用于癌症研究和神经生物学研究[3-4]。
在体外，GW441756（0-15μM）处理RD-ES和SK-ES-1尤文肉瘤细胞72小时。GW441756能显著抑制细胞增殖。GW441756与TrkB选择性抑制剂Ana-12联合使用时，GW441756可产生比单一抑制剂更强的抗增殖效果[5]。GW441756（1μM）预处理PC12细胞4小时，随后以神经生长因子NGF（50ng/mL）刺激24小时。GW441756完全抑制神经生长因子诱导的神经突生长，同时阻断Rivastigmine对神经突生长的增强效应[6]。
在体内，在CLP诱导的脓毒症模型小鼠手术前2天，GW441756（10mg/kg/天）连续腹腔注射小鼠22天。GW441756完全消除了阿米替林对神经元丢失、胶质增生、认知功能障碍和氧化应激的保护作用，并阻断了阿米替林对Akt/GSK3β信号通路和caspase-3表达的调节[7]。GW441756（1-100μM; 10μl）每天鞘内注射一次，用于处理SMIR（皮肤/肌肉切口和牵拉）手术诱导的慢性术后疼痛模型大鼠，从手术后第10天持续处理至第14天。GW441756显著减轻了机械性痛觉过敏，并抑制了背根神经节中Nav1.7、SGK1和p-Nedd4-2的表达上调[8]。