high affinity nerve growth factor receptor|high-affinity, slow-dissociating NGF receptor|MTC|neurotrophic tyrosine kinase|p140-TrkA|Tkr|TRK|tropomyosin-related kinase A Description: Identification and structure of the nerve growth factor binding site on TrkA. Download all structure-activity data for this target as a CSV file Description: In a biochemical assay measuring inhibition of peptide substrate phosphorylation by the test compound in the presence ot recombinant human TrkA. Description: In an Alphascreen assay using intracellular domain of a HIS-tagged human Trk A kinase (amino acids 442-796). EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1 M and 10 M against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5 M against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform. http://www.millipore.com/techpublications/tech1/pf3036 http://www.reactionbiology.com/webapps/main/pages/kinase.aspx Clinically-Relevant Mutations and Pathophysiology Synonyms: Hereditary sensory and autonomic neuropathy [Disease Ontology: DOID:11533] Synonyms: Hereditary sensory and autonomic neuropathy [Disease Ontology: DOID:11533]Hereditary sensory and autonomic neuropathy type 4 [Orphanet: ORPHA642] Synonyms: Familial medullary thyroid carcinoma [Disease Ontology: DOID:0050547] Synonyms: Differentiated thyroid carcinoma [Orphanet: ORPHA146]Papillary thyroid carcinoma [Disease Ontology: DOID:3969] 1. Albaugh P, Fan Y, Mi Y, Sun F, Adrian F, Li N, Jia Y, Sarkisova Y, Kreusch A, Hood T et al..(2012)Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models. 2. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR.(2011)Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. 3. Artim SC, Mendrola JM, Lemmon MA.(2012)Assessing the range of kinase autoinhibition mechanisms in the insulin receptor family. 5. Bertrand T, Kothe M, Liu J, Dupuy A, Rak A, Berne PF, Davis S, Gladysheva T, Valtre C, Crenne JY et al..(2012)The crystal structures of TrkA and TrkB suggest key regions for achieving selective inhibition. 6. Brasca MG, Amboldi N, Ballinari D, Cameron A, Casale E, Cervi G, Colombo M, Colotta F, Croci V, D\'Alessio R et al..(2009)Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. 7. Davies A, Ioannidis S, Lamb M, Su M, Wang T, Zhang H-J.(2013)9-(pyrazol-3-yl)-9H-purine-2-amine and 3-(pyrazol-3-yl) -3H-imidazo[4,5-B] pyridin-5-amine derivatives and their use for the treatment of cancer. Patent number: US8486966B2. Assignee: AstraZeneca AB.Priority date: 04/05/2007. Publication date: 17/07/2013.8. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.(2011)Comprehensive analysis of kinase inhibitor selectivity. 9. Drilon A, Ou SI, Cho BC, Kim DW, Lee J, Lin JJ, Zhu VW, Ahn MJ, Camidge DR, Nguyen J et al..(2018)Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations. 10. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ.(2013)A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. 11. Haas J, Andrews SW, Jiang Y, Zhang G.(2010)Substituted pyrazolo[1,5-a]pyrimidine compounds as TRK kinase inhibitors. Patent number: WO2010048314 A1. Assignee: Array Biopharma Inc..Priority date: 22/10/2008. Publication date: 29/04/2010.12. Hudkins RL, Becknell NC, Zulli AL, Underiner TL, Angeles TS, Aimone LD, Albom MS, Chang H, Miknyoczki SJ, Hunter K et al..(2012)Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): a novel oncology therapeutic agent. 13. Iida H, Fujikawa R, Kozaki R, Harada R, Hosokawa Y, Ogawara K, Ohno T.(2020)Pharmacokinetic-Pharmacodynamic-Efficacy Modeling of ONO-7579, a Novel Pan-TRK Inhibitor, in a Murine Xenograft Tumor Model. 14. Kane JL Jr, Matthews G, Metz M, Kothe M, Liu J, Scholte A.(2015)Tropomyosin-related kinase (Trk) inhibitors. Patent number: US9174986B2. Assignee: Genzyme Corp..Priority date: 10/12/2013. Publication date: 03/11/2015.15. Lee LY, Hernandez D, Rajkhowa T, Smith SC, Raman JR, Nguyen B, Small D, Levis M.(2017)Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. 16. Li Y, Xiong Y, Zhang G, Zhang L, Yang W, Yang J, Huang L, Qiao Z, Miao Z, Lin G et al..(2018)Identification of 5-(2,3-Dihydro-1 H-indol-5-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model. 17. Manthey CL, Johnson DL, Illig CR, Tuman RW, Zhou Z, Baker JF, Chaikin MA, Donatelli RR, Franks CF, Zeng L et al..(2009)JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia. 18. Nanda N, Bilenker JH, Doebele RC, Blake JF, Kolakowski GR, Brandhuber BJ, Andrews SW.(2017)Point mutations in trk inhibitor-resistant cancer and methods relating to the same. Patent number: WO2017075107A1. Assignee: Array Biopharma Inc, Loxo Oncology Inc.Priority date: 26/10/2015. Publication date: 04/05/2017.19. Pan BS, Chan GK, Chenard M, Chi A, Davis LJ, Deshmukh SV, Gibbs JB, Gil S, Hang G, Hatch H et al..(2010)MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. 20. Patwardhan PP, Ivy KS, Musi E, de Stanchina E, Schwartz GK.(2016)Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma. 21. Robertson AG, Banfield MJ, Allen SJ, Dando JA, Mason GG, Tyler SJ, Bennett GS, Brain SD, Clarke AR, Naylor RL et al..(2001)Identification and structure of the nerve growth factor binding site on TrkA. 22. Wang T, Ioannidis S, Almeida L, Block MH, Davies AM, Lamb ML, Scott DA, Su M, Zhang HJ, Alimzhanov M et al..(2011)In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors. 23. Wang T, Lamb ML, Block MH, Davies AM, Han Y, Hoffmann E, Ioannidis S, Josey JA, Liu ZY, Lyne PD et al..(2012)Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors. 24. Wang Z, Zhang Y, Pinkas DM, Fox AE, Luo J, Huang H, Cui S, Xiang Q, Xu T, Xun Q et al..(2018)Design, Synthesis, and Biological Evaluation of 3-(Imidazo[1,2- a]pyrazin-3-ylethynyl)-4-isopropyl- N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide as a Dual Inhibitor of Discoidin Domain Receptors 1 and 2. 25. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al..(2010)Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Type VII RTKs: Neurotrophin receptor/Trk family: neurotrophic receptor tyrosine kinase 1. Last modified on 08/04/2020. Accessed on 18/05/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1817.

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