4otf

Crystal structure of the kinase domain of Bruton's Tyrosine kinase with GDC0834

spinqualitylabelsall models 4otf, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4otf is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 2VL, SO4 NonStd Res: OCS Related: 3ocs, 3oct, 3p03 Gene: AGMX1, ATK, BPK, BTK (HUMAN) Activity: Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [BTK_HUMAN] Defects in BTK are the cause of X-linked agammaglobulinemia (XLA) [MIM:300755]; also known as X-linked agammaglobulinemia type 1 (AGMX1) or immunodeficiency type 1 (IMD1). XLA is a humoral immunodeficiency disease which results in developmental defects in the maturation pathway of B-cells. Affected boys have normal levels of pre-B-cells in their bone marrow but virtually no circulating mature B-lymphocytes. This results in a lack of immunoglobulins of all classes and leads to recurrent bacterial infections like otitis, conjunctivitis, dermatitis, sinusitis in the first few years of life, or even some patients present overwhelming sepsis or meningitis, resulting in death in a few hours. Treatment in most cases is by infusion of intravenous immunoglobulin. Defects in BTK may be the cause of X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD) [MIM:307200]; also known as agammaglobulinemia and isolated growth hormone deficiency or Fleisher syndrome or isolated growth hormone deficiency type 3 (IGHD3). In rare cases XLA is inherited together with isolated growth hormone deficiency (IGHD). Function [BTK_HUMAN] Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis. Publication Abstract from PubMed SAR studies focused on improving the pharmacokinetic (PK) properties of the previously reported potent and selective Btk inhibitor CGI-1746 (1) resulted in the clinical candidate GDC-0834 (2), which retained the potency and selectivity of CGI-1746, but with much improved PK in preclinical animal models. Structure based design efforts drove this work as modifications to 1 were investigated at both the solvent exposed region as well as 'H3 binding pocket'. However, in vitro metabolic evaluation of 2 revealed a non CYP-mediated metabolic process that was more prevalent in human than preclinical species (mouse, rat, dog, cyno), leading to a high-level of uncertainly in predicting human pharmacokinetics. Due to its promising potency, selectivity, and preclinical efficacy, a single dose IND was filed and 2 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, 2 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure. This information informed the back-up program and discovery of improved inhibitors. Potent and selective Bruton's tyrosine kinase inhibitors: Discovery of GDC-0834.,Young WB, Barbosa J, Blomgren P, Bremer MC, Crawford JJ, Dambach D, Gallion S, Hymowitz SG, Kropf JE, Lee SH, Liu L, Lubach JW, Macaluso J, Maciejewski P, Maurer B, Mitchell SA, Ortwine DF, Di Paolo J, Reif K, Scheerens H, Schmitt A, Sowell CG, Wang X, Wong H, Xiong JM, Xu J, Zhao Z, Currie KS Bioorg Med Chem Lett. 2015 Mar 15;25(6):1333-7. doi: 10.1016/j.bmcl.2015.01.032. , Epub 2015 Feb 7. PMID:25701252 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tyrosine kinase

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