trka-in-1

TrkA-IN-1 is a potent and selective inhibitor of Tropomyosin-related kinase A (TrkA) (IC50: 99 nM in a cell-based assay) with analgesic activity.

ITK TRKA-IN-1 is a chemical compound that functions as a dual inhibitor of IL-2-inducible T-cell kinase (ITK) and tropomyosin receptor kinase A (TRKA). With an IC50 value of 1.0 nM, it effectively inhibits the activity of ITK, while demonstrating a remarkable 96% inhibition of TRKA.

FLT3 TrKA-IN-1 是一种有效的 FLT3 TrKA 双激酶抑制剂，能够作用于 FLT3 (IC50: 43.8 nM)、FLT3-ITD (IC50: 97.2 nM)、FLT3-TKD (IC50: 92.5 nM) 和 TrKA (IC50: 23.6 nM)。FLT3 TrKA-IN-1 能够将细胞周期阻滞在 G0 G1 期，并诱导细胞凋亡 (apoptosis)，具有抗增殖作用。FLT3 TrKA-IN-1 具有潜力进行急性髓性白血病 (AML) 的研究。

hTrkA-IN-1 is a potent and orally active inhibitor of TrkA kinase with an IC 50 of 1.3 nM, compound 2.hTrkA-IN-1 can be used for the study of inflammatory disease, such as prostatitis, pelvic, et al.

RIPK1-IN-7 是一种选择性有效的 RIPK1 抑制剂，Kd 值为 4 nM，IC50值为 11 nM。在实验性 B16 黑色素瘤肺转移模型中表现出优异的抗转移活性。

TrkA-IN-8 (Compound 2) 是一种抑制TrkA的抑制剂，其Kd值为3.3 µM。RTKs-IN-1 在肺癌细胞系中表现出浓度依赖性的细胞生长抑制作用，并可能应用于非小细胞肺癌的研究。

Ganglioside GM1is a monosialylated ganglioside and the prototypic ganglioside for those containing one sialic acid residue.1,2It is found in a large variety of cells, including immune cells and neurons, and is enriched in lipid rafts in the cell membrane.3It associates with growth factor receptors, including TrkA, TrkB, and the GDNF receptor complex containing Ret and GFRα, and is required for TrkA expression on the cell surface. Ganglioside GM1interacts with other proteins to increase calcium influx, affecting various calcium-dependent processes, including inducing neuronal outgrowth during differentiation. Ganglioside GM1acts as a receptor for cholera toxin, which binds to its oligosaccharide group, facilitating toxin cell entry into epithelial cells of the jejunum.4,5Similarly, it is bound by the heat-labile enterotoxin fromE. coliin the pathogenesis of traveler's diarrhea.6Ganglioside GM1gangliosidosis, characterized by a deficiency in GM1-β-galactosidase, the enzyme that degrades ganglioside GM1, leads to accumulation of the gangliosides GM1and GA1in neurons and can be fatal in infants.1Levels of ganglioside GM1are decreased in the substantia nigra pars compacta in postmortem brain from patients with Parkinson's disease.3Ganglioside GM1mixture contains a mixture of ovine ganglioside GM1molecular species with primarily C18:0 fatty acyl chain lengths, among various others. [Matreya, LLC. Catalog No. 1544] 1.Kolter, T.Ganglioside biochemistryISRN Biochem.506160(2012) 2.Mocchetti, I.Exogenous gangliosides, neuronal plasticity and repair, and the neurotrophinsCell Mol. Life Sci.62(19-20)2283-2294(2005) 3.Ledeen, R.W., and Wu, G.The multi-tasked life of GM1 ganglioside, a true factotum of natureTrends Biochem. Sci.40(7)407-418(2015) 4.Turnbull, W.B., Precious, B.L., and Homans, S.W.Dissecting the cholera toxin-ganglioside GM1 interaction by isothermal titration calorimetryJ. Am. Chem. Soc.126(4)1047-1054(2004) 5.Blank, N., Schiller, M., Krienke, S., et al.Cholera toxin binds to lipid rafts but has a limited specificity for ganglioside GM1Immunol. Cell Biol.85(5)378-382(2007) 6.Minke, W.E., Roach, C., Hol, W.G., et al.Structure-based exploration of the ganglioside GM1 binding sites of Escherichia coli heat-labile enterotoxin and cholera toxin for the discovery of receptor antagonistsBiochemistry38(18)5684-5692(1999)

ALK-IN-9 (compound 40) is a highly effective ALK inhibitor. It demonstrates remarkable inhibitory activity against cell proliferation, with IC50 values of <0.2 nM for Ba F3-EML4-ALK, KM 12 (TPM3-TRKA), and KG-l cell (OP2-FGFR1).

Trk-IN-7 (compound I-6) is a highly potent inhibitor of TRK, exhibiting IC50 values ranging from 0.25-10 nM for TRKA, TRKB, and TRKC, respectively. In addition, Trk-IN-7 demonstrates notable inhibition against EML4-ALK (IC50 <15 nM), as well as ALK G1202R, ALK C1156Y, ALK R1275Q, ALK F1174L, ALK L1197M, and ALK G1269A (IC50 = 5-50 nM) [1].

Trk-IN-20 is a 3-vinylindazole derivative compound that effectively inhibits the functions of Trk kinases. It accomplishes this by suppressing the phosphorylation of TrkA, TrkB, and TrkC, with IC50 values of 1.6 nM, 2.9 nM, and 2.0 nM, respectively [1].

Trk-IN-8, a powerful TRK inhibitor, demonstrates excellent potency against TRKAa, TRKA(G595R), and TRKC(G623R) with IC50 values of 0.42 nM, 0.89 nM, and 1.5 nM, respectively (WO2021115401A1, compound 3) [1].

Trk-IN-10 (Compound 14j) is a highly effective inhibitor of TRK, with an IC50 of 0.86 nM against TrkA and 6.92 nM against TrkA G595R. As an RTK, Trk plays a crucial role as a drug target in solid tumors. Trk-IN-10 (IC50 = 350 nM against ALK) demonstrates superior selectivity in inhibiting Trk, which has potential implications for toxicity reduction [1].

TRK ALK-IN-1 是一种有效的 TRK 和 ALK 双重抑制剂。TRK ALK-IN-1 在酶促测定中与抗增殖活性非常吻合，对 TRKA、ALKIC50值分别为 2.2、9.3 和 38 nM< sup>WT 和 ALKL1196M。TRK ALK-IN-1具有研究癌症疾病的潜力。

TRKII-IN-1 是一种有效的 II 型TRK抑制剂，对TRKA B C及TRKAG667C的IC50分别为3.3、6.4、4.3 和 9.4 nM。此外，TRKII-IN-1 对FLT3、RET和VEGFR2也具有抑制作用，其IC50分别为1.3、9.9 和 71.1 nM。TRKII-IN-1 主要用于TRK驱动的癌症研究。

TrkA-IN-4 是一种有效和具有口服活性的 TrkA 变构抑制剂，是TrkA-IN-3 的前药。TrkA-IN-4 显示出有效的抗伤害作用。

Bedinvetmab (ZTS-00508841)为针对神经生长因子(NGF)的犬单克隆抗体(mAb)，通过抑制NGF与肌球蛋白原受体激酶A(trkA)及p75神经营养蛋白受体(p75NTR)的相互作用，应用于犬骨关节炎疼痛的研究。

TRAF6 peptide TFA是一种抑制TRAF6-p62相互作用的特异性分子，可抑制NGF依赖的TrkA泛素化，展现在阿尔茨海默症（AD）、帕金森病、ALS、创伤性脑损伤、癫痫和中风等神经系统疾病研究中的应用潜力。

Tanezumab (RN-624) 是一种针对神经生长因子（NGF）的人源化单克隆抗体，具有高度的亲和力和特异性，它通过阻断NGF与p75和TrkA受体的结合来发挥作用，这些受体存在于周围神经系统中。Tanezumab 主要用于研究治疗各种急性及慢性疼痛症状，包括骨关节炎、膝关节炎、神经痛以及带状疱疹后神经痛。

TRK-IN-23 (compound 24b) 是一款口服活性TRK抑制剂，对TRKA、TRKC、TRKAG595R、TRKAF589L和TRKAG667C 表现出高效的抑制作用，其IC50值分别为0.5 nM、9 nM、14 nM、4.4 nM和4.8 nM。此外，TRK-IN-23 能够诱导含有TRKAG595R和TRKAG667C突变的Ba F3细胞系进行细胞凋亡(apoptosis)。

TRK-IN-24（compound 10g）是一种针对Trk Receptor的抑制剂，它对TRKA、TRKC、TRKAG595R、TRKAG667C和TRKAF589L的抑制作用的IC50值分别达到5.21、4.51、6.77、1.42和6.13 nM。该化合物在BaF3-CD74-NTRK1G595R和BaF3-CD74-NTRK1G667C异种移植模型中显示出明显的抗肿瘤活性。此外，TRK-IN-24 能有效抑制携带SF、GK、xDFG等单点突变的Ba F3细胞增殖，其IC50范围为1.43至47.56 nM。

Multi-kinase-IN-6 (compound 10e) 是一种效能极高的多激酶抑制剂，具有对 TrkA、ALK2、c-KIT、EGFR、PIM1、CK2α、CHK1 和 CDK2 等多种酶的显著抑制作用。在 MCF7、HCT116 和 EKVX 癌细胞系上，其抗增殖活性突出，IC50 值分别达到 3.36 μM、1.40 μM 与 3.49 μM。此外，Multi-kinase-IN-6 能引起 MCF7 与 HCT116 细胞的细胞周期在 G1 S 期及 G1 期停滞，并有效诱导凋亡。

Gambogic amide acts as a potent and selective agonist for TrkA, promoting tyrosine phosphorylation and activating downstream signaling pathways such as Akt and MAPK. It specifically binds to the cytoplasmic juxtamembrane domain of the TrkA receptor, stimulating dimerization and activation. The compound demonstrates neuroprotective properties by preventing neuronal cell death caused by glutamate. Additionally, gambogic amide shows enhanced efficacy in a transient middle cerebral artery occlusion model of stroke and may be useful for investigating neurodegenerative diseases and stroke [1].

TRK-IN-28（compound 30f）作为一种TRK抑制剂，对TRKWT、TRKG595R和TRKG667C的IC50值具体表现为0.55 nM、25.1 nM和5.4 nM。同时，此化合物能够抑制多种细胞株的增殖，包括Ba F3 - ETV6 -TRKAWT、Ba F3-ETV6-TRKBWT、Ba F3-LMNA-TRKG595R和Ba F3-LMNA-TRKAG667C，其对应IC50值为9.5 nM、3.7 nM、205.0 nM和48.3 nM。

IGF-1Rmodulator 1 (Example 5) 是一种具有选择性的IGF-1R调节剂，展示出以下EC50值：0.25 μM (IGF1R)、0.29 μM (FGFR1)、0.34 μM (TrkA) 以及0.39 μM (TrkB)。该化合物主要用于针对神经营养因子和 或其他营养因子信号传递机制受损的疾病，如阿尔茨海默病等，进行相关的研究应用。