2ofv
From Proteopedia
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crystal structure of aminoquinazoline 1 bound to Lck
Contents |
Overview
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of, the Src family expressed in T cells and natural killer (NK) cells. Genetic, evidence in both mice and humans demonstrates that Lck kinase activity is, critical for signaling mediated by the T cell receptor (TCR), which leads, to normal T cell development and activation. Selective inhibition of Lck, is expected to offer a new therapy for the treatment of T-cell-mediated, autoimmune and inflammatory disease. Screening of our kinase-preferred, collection identified aminoquinazoline 1 as a potent, nonselective, inhibitor of Lck and T cell proliferation. In this report, we describe the, synthesis and structure-activity relationships of a series of novel, aminoquinazolines possessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibit anti-inflammatory activity, (ED(50) of 22 and 11 mg/kg, respectively) in the anti-CD3-induced, production of interleukin-2 (IL-2) in mice.
Disease
Known disease associated with this structure: SCID due to LCK deficiency OMIM:[153390]
About this Structure
2OFV is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Full crystallographic information is available from OCA.
Reference
Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity., DiMauro EF, Newcomb J, Nunes JJ, Bemis JE, Boucher C, Buchanan JL, Buckner WH, Cee VJ, Chai L, Deak HL, Epstein LF, Faust T, Gallant P, Geuns-Meyer SD, Gore A, Gu Y, Henkle B, Hodous BL, Hsieh F, Huang X, Kim JL, Lee JH, Martin MW, Masse CE, McGowan DC, Metz D, Mohn D, Morgenstern KA, Oliveira-dos-Santos A, Patel VF, Powers D, Rose PE, Schneider S, Tomlinson SA, Tudor YY, Turci SM, Welcher AA, White RD, Zhao H, Zhu L, Zhu X, J Med Chem. 2006 Sep 21;49(19):5671-86. PMID:16970394
Page seeded by OCA on Fri Feb 15 17:40:20 2008
