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 ITK activity and demonstrates a remarkable 96% inhibition of TRKA.

FLT3 TrKA-IN-1 is a potent dual kinase inhibitor that targets FLT3 (IC50: 43.8 nM), FLT3-ITD (IC50: 97.2 nM), FLT3-TKD (IC50: 92.5 nM), and TrKA (IC50: 23.6 nM). FLT3 TrKA-IN-1 shows potential for acute myeloid leukaemia (AML) studies.

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.

DS-1205 is a potent and selective inhibitor of AXL kinase, with an IC50 of 1.3 nM. DS-1205 also inhibits MER, MET, and TRKA, with IC50s of 63, 104, and 407 nM, respectively. DS-1205 can inhibit cell migration in vitro and tumor growth in vivo[1].

RIPK1-IN-7 is a potent and selective inhibitor of RIPK1 (Kd of 4 nM and enzymatic IC50 of 11 nM), exhibiting excellent antimetastasis activity in the experimental B16 melanoma lung metastasis model.

TrkA-IN-8 (Compound 2) is a TrkA inhibitor with a Kd value of 3.3 µM. RTKs-IN-1 demonstrates a concentration-dependent inhibitory effect on the proliferation of lung cancer cell lines and holds potential for research in non-small cell lung cancer.

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, demonstrating remarkable inhibitory activity against cell proliferation, with IC50 values of <0.2 nM for Ba F3-EML4-ALK, KM 12 (TPM3-TRKA), and KG-1 cell (OP2-FGFR1).

Trk-IN-7 (compound I-6) is a highly potent TRK inhibitor, with IC50 values of 0.25-10 nM for TRKA, TRKB, and TRKC, respectively. It also shows significant inhibition of EML4-ALK (IC50 <15 nM) and ALK mutations G1202R, C1156Y, R1275Q, F1174L, L1197M, and 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 is a crucial drug target in solid tumors. Trk-IN-10 (IC50 = 350 nM against ALK) demonstrates superior selectivity in inhibiting Trk, potentially reducing toxicity [1].

TRK ALK-IN-1 is a potent dual inhibitor of TRK and ALK, exhibiting good correlation between its enzymatic inhibition and anti-proliferative activities, with IC50 values of 2.2 nM for TRKA, 9.3 nM for ALK WT, and 38 nM for ALK L1196M. It holds potential for cancer research applications.

TRK II-IN-1 is a potent type II inhibitor of tropomyosin receptor kinases (TRK), with IC50 values of 3.3, 6.4, 4.3, and 9.4 nM against TRKA, TRKB, TRKC, and the mutant TRKA G667C, respectively. It also exhibits IC50 values of 1.3 nM against FLT3, 9.9 nM against RET, and 71.1 nM against VEGFR2. TRK II-IN-1 primarily serves as a research tool for studying TRK-driven cancers [1].

TrkA-IN-4, a potent and orally active allosteric TrkA inhibitor, is a prodrug of TrkA-IN-3 and exhibits potent antinociceptive effects [1].

Bedinvetmab (ZTS-00508841), a canine monoclonal antibody (mAb) designed to target nerve growth factor (NGF), prevents NGF from interacting with its receptors, tropomyosin receptor kinase A (trkA) and p75 neurotrophin receptor (p75NTR). This compound is utilized in the research of managing osteoarthritis pain in dogs [1] [2].

TRAF6 peptide TFA, a specific inhibitor of the TRAF6-p62 interaction, significantly inhibits NGF-dependent ubiquitination of TrkA. This peptide demonstrates promising research applications in various neurological disorders, including Alzheimer's disease (AD), Parkinson's, ALS, head trauma, epilepsy, and stroke [1].

Tanezumab (RN-624) is a high-affinity, specific humanized anti-NGF monoclonal antibody (mAb) that inhibits nerve growth factor (NGF) from binding to its p75 and TrkA receptors in the peripheral nervous system. It is used in research investigating both acute and chronic pain conditions, including osteoarthritis, knee pain, neuralgia, and post-herpetic neuralgia [1] [2].

TRK-IN-23 (compound 24b) is a potent, orally active TRK inhibitor with IC50s of 0.5 nM for TRKA, 9 nM for TRKC, 14 nM for TRKA G595R, 4.4 nM for TRKA F589L, and 4.8 nM for TRKA G667C. It induces apoptosis in Ba F3-TRKAG595R and Ba F3-TRKAG667C cells [1].

TRK-IN-24 (compound 10g) is a selective inhibitor of Trk receptors, effectively targeting TRKA, TRKC, and mutant forms TRKA G595R, TRKA G667C, and TRKA F589L, with corresponding IC50 values of 5.21, 4.51, 6.77, 1.42, and 6.13 nM. It demonstrates antitumor activity in BaF3-CD74-NTRK1 G595R and BaF3-CD74-NTRK1 G667C xenograft models and inhibits the proliferation of Ba F3 cells expressing single mutants SF, GK, and xDFG, with an IC50 range of 1.43-47.56 nM [1].

Multi-kinase-IN-6 (compound 10e) is a multikinase inhibitor that impedes the activity of TrkA, ALK2, c-KIT, EGFR, PIM1, CK2α, CHK1, and CDK2. It exhibits antiproliferative effects on MCF7, HCT116, and EKVX cancer cell lines with IC50s of 3.36 μM, 1.40 μM, and 3.49 μM, respectively. Additionally, Multi-kinase-IN-6 induces cell cycle arrest at the G1 S and G1 phases in MCF7 and HCT116 cells, respectively, and effectively triggers apoptosis [1].

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) functions as a TRK inhibitor, displaying potencies with IC 50 values of 0.55 nM for TRK WT, 25.1 nM for TRK G595R, and 5.4 nM for TRK G667C. Another TRK inhibitor, TRK-IN-2, exhibits antiproliferative effects with IC 50 values against multiple cell lines: 9.5 nM for Ba F3-ETV6-TRKA WT, 3.7 nM for Ba F3-ETV6-TRKB WT, 205.0 nM for Ba F3-LMNA-TRK G595R, and 48.3 nM for Ba F3-LMNA-TRKA G667C [1].