6gql

Crystal structure of human c-KIT kinase domain in complex with AZD3229-analogue (compound 35)Crystal structure of human c-KIT kinase domain in complex with AZD3229-analogue (compound 35)

Structural highlights 6gql is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: Gene: KIT, SCFR (HUMAN) Activity: Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [KIT_HUMAN] Defects in KIT are a cause of piebald trait (PBT) [MIM:172800]; also known as piebaldism. PBT is an autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes. Defects in KIT are a cause of gastrointestinal stromal tumor (GIST) [MIM:606764]. Defects in KIT have been associated with testicular germ cell tumor (TGCT) [MIM:273300]. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms. Defects in KIT are a cause of acute myelogenous leukemia (AML) [MIM:601626]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase. Function [KIT_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1. Publication Abstract from PubMed While the treatment of Gastrointestinal Stromal Tumors (GIST) has been revolutionised by the application of targeted tyrosine kinase inhibitors capable of inhibiting KIT-driven proliferation, diverse mutations to this kinase drive resistance to established therapies. Here we describe the identification of potent pan-KIT mutant kinase inhibitors that can be dosed without being limited by the tolerability issues seen with multi-targeted agents. This effort focussed on identification and optimisation of an existing kinase scaffold through the use of structure-based design. Starting from a series of previously reported phenoxyquinazoline and quinoline based inhibitors of the tyrosine kinase PDGFR, potency against a diverse panel of mutant KIT driven Ba/F3 cell lines was optimised, with a particular focus on reducing activity against a KDR driven cell model in order to limit the potential for hypertension commonly seen in second and third line GIST therapies. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalised predominantly by the interaction of water molecules with the protein and ligand in the active site and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST. Discovery of N-{4-[(6,7-dimethoxyquinazolin-4-yl)oxy]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triaz ol-1-yl]acetamide (AZD3229), a potent pan-KIT mutant inhibitor for the treatment of gastrointestinal stromal tumors.,Kettle JG, Anjum R, Barry E, Bhavsar D, Brown C, Boyd S, Campbell A, Goldberg K, Grondine M, Guichard S, Hardy C, Hunt T, Jones R, Li X, Moleva O, Ogg D, Overman R, Packer MJ, Pearson S, Schimpl M, Shao W, Smith A, Smith J, Stead D, Stokes S, Tucker M, Ye Y J Med Chem. 2018 Sep 11. doi: 10.1021/acs.jmedchem.8b00938. PMID:30204441 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tyrosine kinase

spinqualitylabelsall models 6gql, resolution 2.01Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image