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Xianyun Jiao,
David J Kopecky,
Jinsong Liu, Jinqian Liu,
Juan C Jaen,
Mario G Cardozo,
Rajiv Sharma,
Nigel Walker,
Holger Wesche,
Shyun Li,
Ellyn Farrelly,
Shou-Hua Xiao,
Zhulun Wang,
Frank Kayser
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ABSTRACT: Two classes of ACK1 inhibitors, 4,5,6-trisubstituted furo[2,3-d]pyrimidin4-amines and 4,5,6-trisubstituted 7H-pyrrolo[2,3-d]pyrimidin-4-amines, were discovered and evaluated as ACK1 inhibitors. Further structural refinement led to the identification of potent and selective dithiolane inhibitor 37.
Bioorganic & medicinal chemistry letters 08/2012; 22(19):6212-7. · 2.65 Impact Factor
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Jonathan B Houze,
Liusheng Zhu,
Ying Sun,
Michelle Akerman,
Wei Qiu,
Alex J Zhang,
Rajiv Sharma,
Michael Schmitt,
Yingcai Wang,
Jiwen Liu, [......],
Jane Zhang,
Jenny Ying-Lin Lu,
Michael Chen,
Edwin Lopez,
Kathy Nguyen,
Li Yang,
Liang Tang,
Hui Tian,
Steven J Shuttleworth,
Daniel C-H Lin
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ABSTRACT: The discovery that certain long chain fatty acids potentiate glucose stimulated insulin secretion through the previously orphan receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents. Optimization of a series of β-substituted phenylpropanoic acids led to the identification of (S)-3-(4-((4'-(trifluoromethyl)biphenyl-3-yl)methoxy)phenyl)hex-4-ynoic acid (AMG 837) as a potent GPR40 agonist with a superior pharmacokinetic profile and robust glucose-dependent stimulation of insulin secretion in rodents.
Bioorganic & medicinal chemistry letters 11/2011; 22(2):1267-70. · 2.65 Impact Factor
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Shou-Hua Xiao,
Ellyn Farrelly,
John Anzola,
Daniel Crawford,
Xianyun Jiao, Jinqian Liu,
Merrill Ayres,
Shyun Li,
Linda Huang,
Rajiv Sharma,
Frank Kayser,
Holger Wesche,
Stephen W Young
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ABSTRACT: Several drugs inhibiting protein kinases have been launched successfully, demonstrating the attractiveness of protein kinases as therapeutic targets. Functional genomics research within both academia and industry has led to the identification of many more kinases as potential drug targets. Although a number of well-known formats are used for measuring protein kinase activity, some less well-characterized protein kinases identified through functional genomics present particular challenges for existing assay formats when there is limited knowledge of the endogenous substrates or activation mechanisms for these novel kinase targets. This is especially the case when a very sensitive assay is required to differentiate often highly potent inhibitors developed by late-stage medicinal chemistry programs. ACK1 is a non-receptor tyrosine kinase that has been shown to be involved in tumorigenesis and metastasis. Here we describe the development of an extremely sensitive high-throughput assay for ACK1 capable of detecting 240 fmol per well of the kinase reaction product employing a BV-tag-based electrochemiluminescence assay. This assay is universally applicable to protein tyrosine kinases using a BV-tag-labeled monoclonal antibody against phosphotyrosine. Furthermore, this assay can be extended to the evaluation of Ser/Thr kinases in those cases where an antibody recognizing the phospho-product is available.
Analytical Biochemistry 09/2007; 367(2):179-89. · 3.00 Impact Factor
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ABSTRACT: High-throughput screening of a small-molecule compound library resulted in the identification of a novel series of N-acyl 2-aminobenzimidazoles that are potent inhibitors of interleukin-1 receptor-associated kinase-4.
Bioorganic & Medicinal Chemistry Letters 07/2006; 16(11):2842-5. · 2.55 Impact Factor
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Jay P Powers,
Derek E Piper,
Yang Li,
Veronica Mayorga,
John Anzola,
James M Chen,
Juan C Jaen,
Gary Lee, Jinqian Liu,
M Greg Peterson,
George R Tonn,
Qiuping Ye,
Nigel P C Walker,
Zhulun Wang
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ABSTRACT: Novel non-nucleoside inhibitors of the HCV RNA polymerase (NS5b) with sub-micromolar biochemical potency have been identified which are selective for the inhibition of HCV NS5b over other polymerases. The structures of the complexes formed between several of these inhibitors and HCV NS5b were determined by X-ray crystallography, and the inhibitors were found to bind in an allosteric binding site separate from the active site. Structure-activity relationships and structural studies have identified the mechanism of action for compounds in this series, several of which possess drug-like properties, as unique, reversible, covalent inhibitors of HCV NS5b.
Journal of Medicinal Chemistry 03/2006; 49(3):1034-46. · 5.25 Impact Factor
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ABSTRACT: This review chronicles original literature dating back to 1992 outlining the applications of parallel synthesis and combinatorial chemistry to the synthesis of compound libraries focused towards specific superfamilies of molecular targets. Target families that have received significant literature coverage include kinases, proteases, nuclear hormone receptors and cell surface receptors, notably GPCRs.
Current Medicinal Chemistry 02/2005; 12(11):1239-81. · 4.86 Impact Factor
