4agw | pdb_00004agw

Discovery of a small molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases

spinqualitylabelsall models 4agw, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4agw is a 2 chain structure with sequence from Gallus gallus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL, MES, NG7 Related: 1prm, 1prl, 1rlq, 1f1w, 1p13, 1srl, 2ptk, 1srm, 1f2f, 1rlp, 1nlp, 1nlo Activity: Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed Many clinically validated kinases, such as BCR-ABL, c-Kit, PDGFR, and EGFR, become resistant to adenosine triphosphate-competitive inhibitors through mutation of the so-called gatekeeper amino acid from a threonine to a large hydrophobic amino acid, such as an isoleucine or methionine. We have developed a new class of adenosine triphosphate competitive inhibitors, exemplified by HG-7-85-01, which is capable of inhibiting T315I- BCR-ABL (clinically observed in chronic myeloid leukemia), T670I-c-Kit (clinically observed in gastrointestinal stromal tumors), and T674I/M-PDGFRalpha (clinically observed in hypereosinophilic syndrome). HG-7-85-01 is unique among all currently reported kinase inhibitors in having the ability to accommodate either a gatekeeper threonine, present in the wild-type forms of these kinases, or a large hydrophobic amino acid without becoming a promiscuous kinase inhibitor. The distinctive ability of HG-7-85-01 to simultaneously inhibit both wild-type and mutant forms of several kinases of clinical relevance is an important step in the development of the next generation of tyrosine kinase inhibitors. Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants.,Weisberg E, Choi HG, Ray A, Barrett R, Zhang J, Sim T, Zhou W, Seeliger M, Cameron M, Azam M, Fletcher JA, Debiec-Rychter M, Mayeda M, Moreno D, Kung AL, Janne PA, Khosravi-Far R, Melo JV, Manley PW, Adamia S, Wu C, Gray N, Griffin JD Blood. 2010 May 27;115(21):4206-16. Epub 2010 Mar 18. PMID:20299508 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Proto-oncogene tyrosine-protein kinase Tyrosine kinase

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