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14 results on '"Kraus, Michelle"'

2. Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain

Author

Bagal, Sharan K., primary, Andrews, Mark, additional, Bechle, Bruce M., additional, Bian, Jianwei, additional, Bilsland, James, additional, Blakemore, David C., additional, Braganza, John F., additional, Bungay, Peter J., additional, Corbett, Matthew S., additional, Cronin, Ciaran N., additional, Cui, Jingrong Jean, additional, Dias, Rebecca, additional, Flanagan, Neil J., additional, Greasley, Samantha E., additional, Grimley, Rachel, additional, James, Kim, additional, Johnson, Eric, additional, Kitching, Linda, additional, Kraus, Michelle L., additional, McAlpine, Indrawan, additional, Nagata, Asako, additional, Ninkovic, Sacha, additional, Omoto, Kiyoyuki, additional, Scales, Stephanie, additional, Skerratt, Sarah E., additional, Sun, Jianmin, additional, Tran-Dubé, Michelle, additional, Waldron, Gareth J., additional, Wang, Fen, additional, and Warmus, Joseph S., additional

Published
2018
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4. Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors

Author

Bagal, Sharan K., primary, Omoto, Kiyoyuki, additional, Blakemore, David C., additional, Bungay, Peter J., additional, Bilsland, James G., additional, Clarke, Philip J., additional, Corbett, Matthew S., additional, Cronin, Ciaran N., additional, Cui, J. Jean, additional, Dias, Rebecca, additional, Flanagan, Neil J., additional, Greasley, Samantha E., additional, Grimley, Rachel, additional, Johnson, Eric, additional, Fengas, David, additional, Kitching, Linda, additional, Kraus, Michelle L., additional, McAlpine, Indrawan, additional, Nagata, Asako, additional, Waldron, Gareth J., additional, and Warmus, Joseph S., additional

Published
2018
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5. Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors

Author

Bagal, Sharan K., Omoto, Kiyoyuki, Blakemore, David C., Bungay, Peter J., Bilsland, James G., Clarke, Philip J., Corbett, Matthew S., Cronin, Ciaran N., Cui, J. Jean, Dias, Rebecca, Flanagan, Neil J., Greasley, Samantha E., Grimley, Rachel, Johnson, Eric, Fengas, David, Kitching, Linda, Kraus, Michelle L., McAlpine, Indrawan, Nagata, Asako, Waldron, Gareth J., and Warmus, Joseph S.

Abstract

Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small molecule inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach. Furthermore, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile. Herein, we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious, and well-tolerated series of allosteric TrkA inhibitors that culminated in the delivery of candidate quality compound 23.

Published
2019
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6. Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1

Author

Schnute, Mark E., primary, McReynolds, Matthew D., additional, Kasten, Tom, additional, Yates, Matthew, additional, Jerome, Gina, additional, Rains, John W., additional, Hall, Troii, additional, Chrencik, Jill, additional, Kraus, Michelle, additional, Cronin, Ciaran N., additional, Saabye, Matthew, additional, Highkin, Maureen K., additional, Broadus, Richard, additional, Ogawa, Shinji, additional, Cukyne, Kristin, additional, Zawadzke, Laura E., additional, Peterkin, Vincent, additional, Iyanar, Kaliapan, additional, Scholten, Jeffrey A., additional, Wendling, Jay, additional, Fujiwara, Hideji, additional, Nemirovskiy, Olga, additional, Wittwer, Arthur J., additional, and Nagiec, Marek M., additional

Published
2012
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7. Discovery of Novel, Potent, and Selective Inhibitors of 3-Phosphoinositide-Dependent Kinase (PDK1)

Author

Murphy, Sean T., primary, Alton, Gordon, additional, Bailey, Simon, additional, Baxi, Sangita M., additional, Burke, Benjamin J., additional, Chappie, Thomas A., additional, Ermolieff, Jacques, additional, Ferre, RoseAnn, additional, Greasley, Samantha, additional, Hickey, Michael, additional, Humphrey, John, additional, Kablaoui, Natasha, additional, Kath, John, additional, Kazmirski, Steven, additional, Kraus, Michelle, additional, Kupchinsky, Stan, additional, Li, John, additional, Lingardo, Laura, additional, Marx, Matthew A., additional, Richter, Dan, additional, Tanis, Steven P., additional, Tran, Khanh, additional, Vernier, William, additional, Xie, Zhi, additional, Yin, Min-Jean, additional, and Yu, Xiao-Hong, additional

Published
2011
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8. Study of the PDK1/AKT signaling pathway using selective PDK1 inhibitors, HCS, and enhanced biochemical assays

Author

Hofler, Alexandra, primary, Nichols, Tim, additional, Grant, Stephan, additional, Lingardo, Laura, additional, Esposito, Edward A., additional, Gridley, Scott, additional, Murphy, Sean T., additional, Kath, John C., additional, Cronin, Ciarán N., additional, Kraus, Michelle, additional, Alton, Gordon, additional, Xie, Zhi, additional, Sutton, Scott, additional, Gehring, Mike, additional, and Ermolieff, Jacques, additional

Published
2011
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10. Structure and Thermodynamic Characterization of the EphB4/Ephrin-B2 Antagonist Peptide Complex Reveals the Determinants for Receptor Specificity

Author

Chrencik, Jill E., primary, Brooun, Alexei, additional, Recht, Michael I., additional, Kraus, Michelle L., additional, Koolpe, Mitchell, additional, Kolatkar, Anand R., additional, Bruce, Richard H., additional, Martiny-Baron, Georg, additional, Widmer, Hans, additional, Pasquale, Elena B., additional, and Kuhn, Peter, additional

Published
2006
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12. Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation.

Author

Aertgeerts, Kathleen, Ye, Sheng, Tennant, Mike G., Kraus, Michelle L., Rogers, Joe, Sang, Bi-Ching, Skene, Robert J., Webb, David R., and Prasad, G. Sridhar

Abstract

Dipeptidyl peptidase IV (DPPIV) is a member of the prolyl oligopeptidase family of serine proteases. DPPIV removes dipeptides from the N terminus of substrates, including many chemokines, neuropeptides, and peptide hormones. Specific inhibition of DPPIV is being investigated in human trials for the treatment of type II diabetes. To understand better the molecular determinants that underlie enzyme catalysis and substrate specificity, we report the crystal structures of DPPIV in the free form and in complex with the first 10 residues of the physiological substrate, Neuropeptide Y (residues 1-10; tNPY). The crystal structure of the free form of the enzyme reveals two potential channels through which substrates could access the active site-a so-called propeller opening, and side opening. The crystal structure of the DPPIV/tNPY complex suggests that bioactive peptides utilize the side opening unique to DPPIV to access the active site. Other structural features in the active site such as the presence of a Glu motif, a well-defined hydrophobic S1 subsite, and minimal long-range interactions explain the substrate recognition and binding properties of DPPIV. Moreover, in the DPPIV/tNPY complex structure, the peptide is not cleaved but trapped in a tetrahedral intermediate that occurs during catalysis. Conformational changes of S630 and H740 between DPPIV in its free form and in complex with tNPY were observed and contribute to the stabilization of the tetrahedral intermediate. Our results facilitate the design of potent, selective small molecule inhibitors of DPPIV that may yield compounds for the development of novel drugs to treat type II diabetes. [ABSTRACT FROM AUTHOR]

Published
2004
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13. Structural and Kinetic Analysis of the Substrate Specificity of Human Fibroblast Activation Protein α.

Author

Aertgeerts, Kathleen, Levin, Irena, Lihong Shi, Snell, Gyorgy P., Jennings, Andy, Prasad, G. Sridhar, Yanmiug Zhang, Kraus, Michelle L., Shant Salakian, Vandana Sridhar, Robert Wijnands, and Mike G. Tennant

Subjects
*FIBROBLASTS, *CONNECTIVE tissue cells, *PROTEINS, *BIOMOLECULES
Abstract

Fibroblast activation protein α (FAPα) is highly expressed in epithelial cancers and has been implicated in extracellular matrix remodeling, tumor growth, and metastasis. We present the first high resolution structure for the apoenzyme as well as kinetic data toward small dipeptide substrates. FAPα exhibits a dipeptidyl peptidase IV (DPPIV)-like fold, featuring an α/β-hydrolase domain and an eight-bladed β-propeller domain. Known DPPIV dipeptides are cleaved by FAPα with an ∼100-fold decrease in catalytic efficiency compared with DPPIV. Moreover, FAPα, but not DPPIV, possesses endopeptidase activity toward N-terminal benzyloxycarbonyl (Z)-blocked peptides. Comparison of the crystal structures of FAPα and DPPIV revealed one major difference in the vicinity of the Glu motif (Glu203-Glu204 for FAPα; Glu205-Glu206 for DPPIV) within the active site of the enzyme. Ala657 in FAPα, instead of Asp663 as in DPPIV, reduces the acidity in this pocket, and this change could explain the lower affinity for N-terminal amines by FAPα. This hypothesis was tested by kinetic analysis of the mutant FAPα/A657D, which shows on average an ∼60-fold increase in the catalytic efficiency, as measured by kcat/Km, for the cleavage of dipeptide substrates. Furthermore, the catalytic efficiency of the mutant is reduced by ∼350-fold for cleavage of Z-Gly-Pro-7-amino-4-methylcoumarin. Our data provide a clear understanding of the molecular determinants responsible for the substrate specificity and endopeptidase activity of FAPα. [ABSTRACT FROM AUTHOR]

Published
2005
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14. Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation.

Author

Aertgeerts K, Ye S, Tennant MG, Kraus ML, Rogers J, Sang BC, Skene RJ, Webb DR, and Prasad GS

Subjects
Animals, Binding Sites, Catalytic Domain, Cells, Cultured, Crystallization, Crystallography, X-Ray, Humans, Insecta, Models, Molecular, Protein Structure, Tertiary, Substrate Specificity, Dipeptidyl Peptidase 4 chemistry, Dipeptidyl Peptidase 4 metabolism, Neuropeptide Y chemistry, Oligopeptides chemistry, Oligopeptides metabolism
Abstract

Dipeptidyl peptidase IV (DPPIV) is a member of the prolyl oligopeptidase family of serine proteases. DPPIV removes dipeptides from the N terminus of substrates, including many chemokines, neuropeptides, and peptide hormones. Specific inhibition of DPPIV is being investigated in human trials for the treatment of type II diabetes. To understand better the molecular determinants that underlie enzyme catalysis and substrate specificity, we report the crystal structures of DPPIV in the free form and in complex with the first 10 residues of the physiological substrate, Neuropeptide Y (residues 1-10; tNPY). The crystal structure of the free form of the enzyme reveals two potential channels through which substrates could access the active site-a so-called propeller opening, and side opening. The crystal structure of the DPPIV/tNPY complex suggests that bioactive peptides utilize the side opening unique to DPPIV to access the active site. Other structural features in the active site such as the presence of a Glu motif, a well-defined hydrophobic S1 subsite, and minimal long-range interactions explain the substrate recognition and binding properties of DPPIV. Moreover, in the DPPIV/tNPY complex structure, the peptide is not cleaved but trapped in a tetrahedral intermediate that occurs during catalysis. Conformational changes of S630 and H740 between DPPIV in its free form and in complex with tNPY were observed and contribute to the stabilization of the tetrahedral intermediate. Our results facilitate the design of potent, selective small molecule inhibitors of DPPIV that may yield compounds for the development of novel drugs to treat type II diabetes.

Published
2004
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