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.

FLT3/TrKA-IN-1 is a potent FLT3/TrKA dual kinase inhibitor, capable of acting on 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 has potential for acute myeloid leukaemia (AML) studies.

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.

Entrectinib (RXDX-101) is an inhibitor of TrkA (IC50: 1.7 nM), TrkB (IC50: 0.1 nM), and TrkC (IC50: 0.1 nM), as well as anaplastic lymphoma kinase (ALK; IC50: 1.6 nM) and C-ros oncogene 1 (ROS1; IC50: 0.2 nM). Entrectinib blocks proliferation of ALK-dependent cell lines, including those with C1156Y or L1196M resistance mutations, and inhibits ALK‐dependent signaling. It has been shown to inhibit the growth of a non-small cell lung Y cell line bearing an EML4-ALK rearrangement. In mice bearing various ROS1, Trk, or ALK-driven xenografts, Entrectinib has been shown to induce tumor regression.

Multi-kinase-IN-6 (compound 10e) is a multikinase inhibitor that effectively 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. Furthermore, Multi-kinase-IN-6 induces cell cycle arrest at the G1/S and G1 phases in MCF7 and HCT116 cells, respectively, and triggers apoptosis effectively [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 utilized in research investigating both acute and chronic pain conditions, including osteoarthritis, knee pain, neuralgia, and post-herpetic neuralgia [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].

TRK II-IN-1 is a potent type II inhibitor of tropomyosin receptor kinases (TRK), demonstrating inhibitory half-maximal inhibitory concentrations (IC50s) of 3.3, 6.4, 4.3, and 9.4 nM against TRKA, TRKB, TRKC, and the mutant TRKA G667C, respectively. Additionally, this compound 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].

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 IC50 values of 5.21, 4.51, 6.77, 1.42, and 6.13 nM, respectively. 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].

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.

TRK-IN-23 (compound 24b) is a potent, orally active inhibitor of TRK 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].

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

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].

CE-245677 is a selective, orally active Tie2 kinase inhibitor identified by Pfizer previously in development for the treatment of certain cancers. CE-245,677 is a potent reversible inhibitor of Tie2 and TrkA/B kinases with a cellular IC50 of 4.7 and 1 nM, resp., displays >100x selectivity against a number of other angiogenic receptor tyrosine kinases (e.g. KDR, PDGFR, FGFR) and gene family panels, and demonstrates good oral absorption in in vivo rat PK studies (F=80%).

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

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].

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].

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)

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-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-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].

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].