4ymj

(R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors

spinqualitylabelsall models 4ymj, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ymj is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2Å Ligands: 4EJ, CL, GOL, SEP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NTRK3_HUMAN Receptor for neurotrophin-3 (NT-3). This is a tyrosine-protein kinase receptor. Known substrates for the trk receptors are SHC1, PI-3 kinase, and PLCG1. The different isoforms do not have identical signaling properties. Publication Abstract from PubMed Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs. (R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.,Choi HS, Rucker PV, Wang Z, Fan Y, Albaugh P, Chopiuk G, Gessier F, Sun F, Adrian F, Liu G, Hood T, Li N, Jia Y, Che J, McCormack S, Li A, Li J, Steffy A, Culazzo A, Tompkins C, Phung V, Kreusch A, Lu M, Hu B, Chaudhary A, Prashad M, Tuntland T, Liu B, Harris J, Seidel HM, Loren J, Molteni V ACS Med Chem Lett. 2015 Mar 16;6(5):562-7. doi: 10.1021/acsmedchemlett.5b00050., eCollection 2015 May 14. PMID:26005534 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also TrkB tyrosine kinase receptor Tyrosine kinase receptor 3D structures

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