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1. Supplementary Table S2 from Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent

Author

Andraos, Rita, primary, Qian, Zhiyan, primary, Bonenfant, Débora, primary, Rubert, Joëlle, primary, Vangrevelinghe, Eric, primary, Scheufler, Clemens, primary, Marque, Fanny, primary, Régnier, Catherine H., primary, De Pover, Alain, primary, Ryckelynck, Hugues, primary, Bhagwat, Neha, primary, Koppikar, Priya, primary, Goel, Aviva, primary, Wyder, Lorenza, primary, Tavares, Gisele, primary, Baffert, Fabienne, primary, Pissot-Soldermann, Carole, primary, Manley, Paul W., primary, Gaul, Christoph, primary, Voshol, Hans, primary, Levine, Ross L., primary, Sellers, William R., primary, Hofmann, Francesco, primary, and Radimerski, Thomas, primary

Published
2023
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2. Data from Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent

Author

Andraos, Rita, primary, Qian, Zhiyan, primary, Bonenfant, Débora, primary, Rubert, Joëlle, primary, Vangrevelinghe, Eric, primary, Scheufler, Clemens, primary, Marque, Fanny, primary, Régnier, Catherine H., primary, De Pover, Alain, primary, Ryckelynck, Hugues, primary, Bhagwat, Neha, primary, Koppikar, Priya, primary, Goel, Aviva, primary, Wyder, Lorenza, primary, Tavares, Gisele, primary, Baffert, Fabienne, primary, Pissot-Soldermann, Carole, primary, Manley, Paul W., primary, Gaul, Christoph, primary, Voshol, Hans, primary, Levine, Ross L., primary, Sellers, William R., primary, Hofmann, Francesco, primary, and Radimerski, Thomas, primary

Published
2023
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3. Supplementary Figure 2 from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

Fritsch, Christine, primary, Huang, Alan, primary, Chatenay-Rivauday, Christian, primary, Schnell, Christian, primary, Reddy, Anupama, primary, Liu, Manway, primary, Kauffmann, Audrey, primary, Guthy, Daniel, primary, Erdmann, Dirk, primary, De Pover, Alain, primary, Furet, Pascal, primary, Gao, Hui, primary, Ferretti, Stephane, primary, Wang, Youzhen, primary, Trappe, Joerg, primary, Brachmann, Saskia M., primary, Maira, Sauveur-Michel, primary, Wilson, Christopher, primary, Boehm, Markus, primary, Garcia-Echeverria, Carlos, primary, Chene, Patrick, primary, Wiesmann, Marion, primary, Cozens, Robert, primary, Lehar, Joseph, primary, Schlegel, Robert, primary, Caravatti, Giorgio, primary, Hofmann, Francesco, primary, and Sellers, William R., primary

Published
2023
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4. Supplementary Figures, Methods, and References from Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent

Author

Andraos, Rita, primary, Qian, Zhiyan, primary, Bonenfant, Débora, primary, Rubert, Joëlle, primary, Vangrevelinghe, Eric, primary, Scheufler, Clemens, primary, Marque, Fanny, primary, Régnier, Catherine H., primary, De Pover, Alain, primary, Ryckelynck, Hugues, primary, Bhagwat, Neha, primary, Koppikar, Priya, primary, Goel, Aviva, primary, Wyder, Lorenza, primary, Tavares, Gisele, primary, Baffert, Fabienne, primary, Pissot-Soldermann, Carole, primary, Manley, Paul W., primary, Gaul, Christoph, primary, Voshol, Hans, primary, Levine, Ross L., primary, Sellers, William R., primary, Hofmann, Francesco, primary, and Radimerski, Thomas, primary

Published
2023
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5. Supplementary Figure 7 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Maira, Sauveur-Michel, primary, Pecchi, Sabina, primary, Huang, Alan, primary, Burger, Matthew, primary, Knapp, Mark, primary, Sterker, Dario, primary, Schnell, Christian, primary, Guthy, Daniel, primary, Nagel, Tobi, primary, Wiesmann, Marion, primary, Brachmann, Saskia, primary, Fritsch, Christine, primary, Dorsch, Marion, primary, Chène, Patrick, primary, Shoemaker, Kevin, primary, De Pover, Alain, primary, Menezes, Daniel, primary, Martiny-Baron, Georg, primary, Fabbro, Doriano, primary, Wilson, Christopher J., primary, Schlegel, Robert, primary, Hofmann, Francesco, primary, García-Echeverría, Carlos, primary, Sellers, William R., primary, and Voliva, Charles F., primary

Published
2023
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6. Supplementary Figure 3 from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

Fritsch, Christine, primary, Huang, Alan, primary, Chatenay-Rivauday, Christian, primary, Schnell, Christian, primary, Reddy, Anupama, primary, Liu, Manway, primary, Kauffmann, Audrey, primary, Guthy, Daniel, primary, Erdmann, Dirk, primary, De Pover, Alain, primary, Furet, Pascal, primary, Gao, Hui, primary, Ferretti, Stephane, primary, Wang, Youzhen, primary, Trappe, Joerg, primary, Brachmann, Saskia M., primary, Maira, Sauveur-Michel, primary, Wilson, Christopher, primary, Boehm, Markus, primary, Garcia-Echeverria, Carlos, primary, Chene, Patrick, primary, Wiesmann, Marion, primary, Cozens, Robert, primary, Lehar, Joseph, primary, Schlegel, Robert, primary, Caravatti, Giorgio, primary, Hofmann, Francesco, primary, and Sellers, William R., primary

Published
2023
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7. Supplementary Figure Legends, Supplementary Table Legends, and Supplementary Tables 1 through 7 from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

Fritsch, Christine, primary, Huang, Alan, primary, Chatenay-Rivauday, Christian, primary, Schnell, Christian, primary, Reddy, Anupama, primary, Liu, Manway, primary, Kauffmann, Audrey, primary, Guthy, Daniel, primary, Erdmann, Dirk, primary, De Pover, Alain, primary, Furet, Pascal, primary, Gao, Hui, primary, Ferretti, Stephane, primary, Wang, Youzhen, primary, Trappe, Joerg, primary, Brachmann, Saskia M., primary, Maira, Sauveur-Michel, primary, Wilson, Christopher, primary, Boehm, Markus, primary, Garcia-Echeverria, Carlos, primary, Chene, Patrick, primary, Wiesmann, Marion, primary, Cozens, Robert, primary, Lehar, Joseph, primary, Schlegel, Robert, primary, Caravatti, Giorgio, primary, Hofmann, Francesco, primary, and Sellers, William R., primary

Published
2023
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8. Supplementary Figure 3 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Maira, Sauveur-Michel, primary, Pecchi, Sabina, primary, Huang, Alan, primary, Burger, Matthew, primary, Knapp, Mark, primary, Sterker, Dario, primary, Schnell, Christian, primary, Guthy, Daniel, primary, Nagel, Tobi, primary, Wiesmann, Marion, primary, Brachmann, Saskia, primary, Fritsch, Christine, primary, Dorsch, Marion, primary, Chène, Patrick, primary, Shoemaker, Kevin, primary, De Pover, Alain, primary, Menezes, Daniel, primary, Martiny-Baron, Georg, primary, Fabbro, Doriano, primary, Wilson, Christopher J., primary, Schlegel, Robert, primary, Hofmann, Francesco, primary, García-Echeverría, Carlos, primary, Sellers, William R., primary, and Voliva, Charles F., primary

Published
2023
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9. Supplementary Figure 4 from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

Fritsch, Christine, primary, Huang, Alan, primary, Chatenay-Rivauday, Christian, primary, Schnell, Christian, primary, Reddy, Anupama, primary, Liu, Manway, primary, Kauffmann, Audrey, primary, Guthy, Daniel, primary, Erdmann, Dirk, primary, De Pover, Alain, primary, Furet, Pascal, primary, Gao, Hui, primary, Ferretti, Stephane, primary, Wang, Youzhen, primary, Trappe, Joerg, primary, Brachmann, Saskia M., primary, Maira, Sauveur-Michel, primary, Wilson, Christopher, primary, Boehm, Markus, primary, Garcia-Echeverria, Carlos, primary, Chene, Patrick, primary, Wiesmann, Marion, primary, Cozens, Robert, primary, Lehar, Joseph, primary, Schlegel, Robert, primary, Caravatti, Giorgio, primary, Hofmann, Francesco, primary, and Sellers, William R., primary

Published
2023
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10. Supplementary Figure 6 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Maira, Sauveur-Michel, primary, Pecchi, Sabina, primary, Huang, Alan, primary, Burger, Matthew, primary, Knapp, Mark, primary, Sterker, Dario, primary, Schnell, Christian, primary, Guthy, Daniel, primary, Nagel, Tobi, primary, Wiesmann, Marion, primary, Brachmann, Saskia, primary, Fritsch, Christine, primary, Dorsch, Marion, primary, Chène, Patrick, primary, Shoemaker, Kevin, primary, De Pover, Alain, primary, Menezes, Daniel, primary, Martiny-Baron, Georg, primary, Fabbro, Doriano, primary, Wilson, Christopher J., primary, Schlegel, Robert, primary, Hofmann, Francesco, primary, García-Echeverría, Carlos, primary, Sellers, William R., primary, and Voliva, Charles F., primary

Published
2023
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11. Supplementary Materials, Tables 1-2, Figure Legends 1-8 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Maira, Sauveur-Michel, primary, Pecchi, Sabina, primary, Huang, Alan, primary, Burger, Matthew, primary, Knapp, Mark, primary, Sterker, Dario, primary, Schnell, Christian, primary, Guthy, Daniel, primary, Nagel, Tobi, primary, Wiesmann, Marion, primary, Brachmann, Saskia, primary, Fritsch, Christine, primary, Dorsch, Marion, primary, Chène, Patrick, primary, Shoemaker, Kevin, primary, De Pover, Alain, primary, Menezes, Daniel, primary, Martiny-Baron, Georg, primary, Fabbro, Doriano, primary, Wilson, Christopher J., primary, Schlegel, Robert, primary, Hofmann, Francesco, primary, García-Echeverría, Carlos, primary, Sellers, William R., primary, and Voliva, Charles F., primary

Published
2023
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12. Supplementary Figure 5 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Maira, Sauveur-Michel, primary, Pecchi, Sabina, primary, Huang, Alan, primary, Burger, Matthew, primary, Knapp, Mark, primary, Sterker, Dario, primary, Schnell, Christian, primary, Guthy, Daniel, primary, Nagel, Tobi, primary, Wiesmann, Marion, primary, Brachmann, Saskia, primary, Fritsch, Christine, primary, Dorsch, Marion, primary, Chène, Patrick, primary, Shoemaker, Kevin, primary, De Pover, Alain, primary, Menezes, Daniel, primary, Martiny-Baron, Georg, primary, Fabbro, Doriano, primary, Wilson, Christopher J., primary, Schlegel, Robert, primary, Hofmann, Francesco, primary, García-Echeverría, Carlos, primary, Sellers, William R., primary, and Voliva, Charles F., primary

Published
2023
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13. Supplementary Figure 8 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Maira, Sauveur-Michel, primary, Pecchi, Sabina, primary, Huang, Alan, primary, Burger, Matthew, primary, Knapp, Mark, primary, Sterker, Dario, primary, Schnell, Christian, primary, Guthy, Daniel, primary, Nagel, Tobi, primary, Wiesmann, Marion, primary, Brachmann, Saskia, primary, Fritsch, Christine, primary, Dorsch, Marion, primary, Chène, Patrick, primary, Shoemaker, Kevin, primary, De Pover, Alain, primary, Menezes, Daniel, primary, Martiny-Baron, Georg, primary, Fabbro, Doriano, primary, Wilson, Christopher J., primary, Schlegel, Robert, primary, Hofmann, Francesco, primary, García-Echeverría, Carlos, primary, Sellers, William R., primary, and Voliva, Charles F., primary

Published
2023
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14. Supplementary Figure 1 from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

Fritsch, Christine, primary, Huang, Alan, primary, Chatenay-Rivauday, Christian, primary, Schnell, Christian, primary, Reddy, Anupama, primary, Liu, Manway, primary, Kauffmann, Audrey, primary, Guthy, Daniel, primary, Erdmann, Dirk, primary, De Pover, Alain, primary, Furet, Pascal, primary, Gao, Hui, primary, Ferretti, Stephane, primary, Wang, Youzhen, primary, Trappe, Joerg, primary, Brachmann, Saskia M., primary, Maira, Sauveur-Michel, primary, Wilson, Christopher, primary, Boehm, Markus, primary, Garcia-Echeverria, Carlos, primary, Chene, Patrick, primary, Wiesmann, Marion, primary, Cozens, Robert, primary, Lehar, Joseph, primary, Schlegel, Robert, primary, Caravatti, Giorgio, primary, Hofmann, Francesco, primary, and Sellers, William R., primary

Published
2023
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15. Supplementary Figure 2 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Maira, Sauveur-Michel, primary, Pecchi, Sabina, primary, Huang, Alan, primary, Burger, Matthew, primary, Knapp, Mark, primary, Sterker, Dario, primary, Schnell, Christian, primary, Guthy, Daniel, primary, Nagel, Tobi, primary, Wiesmann, Marion, primary, Brachmann, Saskia, primary, Fritsch, Christine, primary, Dorsch, Marion, primary, Chène, Patrick, primary, Shoemaker, Kevin, primary, De Pover, Alain, primary, Menezes, Daniel, primary, Martiny-Baron, Georg, primary, Fabbro, Doriano, primary, Wilson, Christopher J., primary, Schlegel, Robert, primary, Hofmann, Francesco, primary, García-Echeverría, Carlos, primary, Sellers, William R., primary, and Voliva, Charles F., primary

Published
2023
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16. Supplementary Figure 1 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Maira, Sauveur-Michel, primary, Pecchi, Sabina, primary, Huang, Alan, primary, Burger, Matthew, primary, Knapp, Mark, primary, Sterker, Dario, primary, Schnell, Christian, primary, Guthy, Daniel, primary, Nagel, Tobi, primary, Wiesmann, Marion, primary, Brachmann, Saskia, primary, Fritsch, Christine, primary, Dorsch, Marion, primary, Chène, Patrick, primary, Shoemaker, Kevin, primary, De Pover, Alain, primary, Menezes, Daniel, primary, Martiny-Baron, Georg, primary, Fabbro, Doriano, primary, Wilson, Christopher J., primary, Schlegel, Robert, primary, Hofmann, Francesco, primary, García-Echeverría, Carlos, primary, Sellers, William R., primary, and Voliva, Charles F., primary

Published
2023
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17. Supplementary Figure 4 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Maira, Sauveur-Michel, primary, Pecchi, Sabina, primary, Huang, Alan, primary, Burger, Matthew, primary, Knapp, Mark, primary, Sterker, Dario, primary, Schnell, Christian, primary, Guthy, Daniel, primary, Nagel, Tobi, primary, Wiesmann, Marion, primary, Brachmann, Saskia, primary, Fritsch, Christine, primary, Dorsch, Marion, primary, Chène, Patrick, primary, Shoemaker, Kevin, primary, De Pover, Alain, primary, Menezes, Daniel, primary, Martiny-Baron, Georg, primary, Fabbro, Doriano, primary, Wilson, Christopher J., primary, Schlegel, Robert, primary, Hofmann, Francesco, primary, García-Echeverría, Carlos, primary, Sellers, William R., primary, and Voliva, Charles F., primary

Published
2023
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18. Supplementary Figure 4 from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

William R. Sellers, Francesco Hofmann, Giorgio Caravatti, Robert Schlegel, Joseph Lehar, Robert Cozens, Marion Wiesmann, Patrick Chene, Carlos Garcia-Echeverria, Markus Boehm, Christopher Wilson, Sauveur-Michel Maira, Saskia M. Brachmann, Joerg Trappe, Youzhen Wang, Stephane Ferretti, Hui Gao, Pascal Furet, Alain De Pover, Dirk Erdmann, Daniel Guthy, Audrey Kauffmann, Manway Liu, Anupama Reddy, Christian Schnell, Christian Chatenay-Rivauday, Alan Huang, and Christine Fritsch

Abstract

PDF - 60K, Linear correlation observed between tumor growth inhibition (% T/C) or tumor regression and the fraction of time over the in vivo S473P-Akt IC80 in different cancer cell line-derived tumor xenografts implanted in nude mice (represented as dots) and nude rats (represented as triangles) following NVP-BYL719 treatment (R2=0.77, p

Published
2023

19. Supplementary Figure 6 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 504K

Published
2023

20. Data from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

William R. Sellers, Francesco Hofmann, Giorgio Caravatti, Robert Schlegel, Joseph Lehar, Robert Cozens, Marion Wiesmann, Patrick Chene, Carlos Garcia-Echeverria, Markus Boehm, Christopher Wilson, Sauveur-Michel Maira, Saskia M. Brachmann, Joerg Trappe, Youzhen Wang, Stephane Ferretti, Hui Gao, Pascal Furet, Alain De Pover, Dirk Erdmann, Daniel Guthy, Audrey Kauffmann, Manway Liu, Anupama Reddy, Christian Schnell, Christian Chatenay-Rivauday, Alan Huang, and Christine Fritsch

Abstract

Somatic PIK3CA mutations are frequently found in solid tumors, raising the hypothesis that selective inhibition of PI3Kα may have robust efficacy in PIK3CA-mutant cancers while sparing patients the side-effects associated with broader inhibition of the class I phosphoinositide 3-kinase (PI3K) family. Here, we report the biologic properties of the 2-aminothiazole derivative NVP-BYL719, a selective inhibitor of PI3Kα and its most common oncogenic mutant forms. The compound selectivity combined with excellent drug-like properties translates to dose- and time-dependent inhibition of PI3Kα signaling in vivo, resulting in robust therapeutic efficacy and tolerability in PIK3CA-dependent tumors. Novel targeted therapeutics such as NVP-BYL719, designed to modulate aberrant functions elicited by cancer-specific genetic alterations upon which the disease depends, require well-defined patient stratification strategies in order to maximize their therapeutic impact and benefit for the patients. Here, we also describe the application of the Cancer Cell Line Encyclopedia as a preclinical platform to refine the patient stratification strategy for NVP-BYL719 and found that PIK3CA mutation was the foremost positive predictor of sensitivity while revealing additional positive and negative associations such as PIK3CA amplification and PTEN mutation, respectively. These patient selection determinants are being assayed in the ongoing NVP-BYL719 clinical trials. Mol Cancer Ther; 13(5); 1117–29. ©2014 AACR.

Published
2023

21. Supplementary Figures, Methods, and References from Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent

Author

Thomas Radimerski, Francesco Hofmann, William R. Sellers, Ross L. Levine, Hans Voshol, Christoph Gaul, Paul W. Manley, Carole Pissot-Soldermann, Fabienne Baffert, Gisele Tavares, Lorenza Wyder, Aviva Goel, Priya Koppikar, Neha Bhagwat, Hugues Ryckelynck, Alain De Pover, Catherine H. Régnier, Fanny Marque, Clemens Scheufler, Eric Vangrevelinghe, Joëlle Rubert, Débora Bonenfant, Zhiyan Qian, and Rita Andraos

Abstract

PDF file - 841K, Supplementary Figures S1-S6; legends for Supplementary Tables S1-S3; Supplementary Methods describing RNA interference, generation of Ba/F3 cell lines, site-directed mutagenesis, transient transfection, inhibition of cellular ATP production, proliferation assays, enzymatic assays with JAK2 JH1, purification of tyrosine phosporylated peptides and mass-spectrometry; Supplementary References.

Published
2023

22. Supplementary Table S1 from Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent

Author

Thomas Radimerski, Francesco Hofmann, William R. Sellers, Ross L. Levine, Hans Voshol, Christoph Gaul, Paul W. Manley, Carole Pissot-Soldermann, Fabienne Baffert, Gisele Tavares, Lorenza Wyder, Aviva Goel, Priya Koppikar, Neha Bhagwat, Hugues Ryckelynck, Alain De Pover, Catherine H. Régnier, Fanny Marque, Clemens Scheufler, Eric Vangrevelinghe, Joëlle Rubert, Débora Bonenfant, Zhiyan Qian, and Rita Andraos

Abstract

PDF file - 11K, Activity of NVP-BBT594 in biochemical and cell-based assays. The IC50 (mean of two experiments) of NVP-BBT594 on the JAK2 kinase was determined in a biochemical kinase assay with the active enzyme. Half-maximal growth inhibition (GI50,) of NVP-BBT594 was determined in SET-2, CMK and K-562 cell lines (mean � SD, n = 4).

Published
2023

23. Supplementary Figure 3 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 215K

Published
2023

24. Supplementary Figure 7 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 579K

Published
2023

25. Supplementary Figure 4 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 766K

Published
2023

26. Supplementary Figure Legends, Supplementary Table Legends, and Supplementary Tables 1 through 7 from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

William R. Sellers, Francesco Hofmann, Giorgio Caravatti, Robert Schlegel, Joseph Lehar, Robert Cozens, Marion Wiesmann, Patrick Chene, Carlos Garcia-Echeverria, Markus Boehm, Christopher Wilson, Sauveur-Michel Maira, Saskia M. Brachmann, Joerg Trappe, Youzhen Wang, Stephane Ferretti, Hui Gao, Pascal Furet, Alain De Pover, Dirk Erdmann, Daniel Guthy, Audrey Kauffmann, Manway Liu, Anupama Reddy, Christian Schnell, Christian Chatenay-Rivauday, Alan Huang, and Christine Fritsch

Abstract

PDF - 129K, Legends for Supplementary Figures 1 through 4 and Supplementary Tables 1 through 7. Supplementary Table 1. Determination of NVP-BYL719 in vitro effects on human protein kinases. Supplementary Table 2. Activity profile of NVP-BYL719 in the Invitrogen Kinase panel. Supplementary Table 3. Activity profile of NVP-BYL719 in the Ambit Kinase panel. Supplementary Table 4. NVP-BYL719 Kd (nmol/L) determination in the Ambit Kinase panel for the hits found to be inhibited >90%. Supplementary Table 5. NVP-BYL719 anti-tumor effects in diverse cancer cell line-derived xenograft models. Supplementary Table 6. CCLE cell lines responsive to NVP-BYL719. Supplementary Table 7 Anti-tumor effect of NVP-BYL719 in patient-derived xenograft models carrying PIK3CA genetic alterations.

Published
2023

27. Supplementary Figure 2 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 253K

Published
2023

28. Supplementary Figure 2 from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

William R. Sellers, Francesco Hofmann, Giorgio Caravatti, Robert Schlegel, Joseph Lehar, Robert Cozens, Marion Wiesmann, Patrick Chene, Carlos Garcia-Echeverria, Markus Boehm, Christopher Wilson, Sauveur-Michel Maira, Saskia M. Brachmann, Joerg Trappe, Youzhen Wang, Stephane Ferretti, Hui Gao, Pascal Furet, Alain De Pover, Dirk Erdmann, Daniel Guthy, Audrey Kauffmann, Manway Liu, Anupama Reddy, Christian Schnell, Christian Chatenay-Rivauday, Alan Huang, and Christine Fritsch

Abstract

PDF - 71K, Rat1-myr-p110alpha (blue), beta (green) or delta (red) cells were treated with increasing concentrations of NVP-BYL719 for 30 minutes. Levels of S473P-Akt in cell extracts were quantified by Reverse Phase Protein Array as described in (18) and plotted as percentage of untreated control cells. The graph illustrates n=3 independent experiments. IC50s (plus/minus) SD and IC80s (plus/minus) SD of n=3 independent experiments are reported..

Published
2023

29. Supplementary Figure 1 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 419K

Published
2023

30. Supplementary Figure 8 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 727K

Published
2023

31. Supplementary Materials, Tables 1-2, Figure Legends 1-8 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 180K

Published
2023

32. Supplementary Figure 3 from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

William R. Sellers, Francesco Hofmann, Giorgio Caravatti, Robert Schlegel, Joseph Lehar, Robert Cozens, Marion Wiesmann, Patrick Chene, Carlos Garcia-Echeverria, Markus Boehm, Christopher Wilson, Sauveur-Michel Maira, Saskia M. Brachmann, Joerg Trappe, Youzhen Wang, Stephane Ferretti, Hui Gao, Pascal Furet, Alain De Pover, Dirk Erdmann, Daniel Guthy, Audrey Kauffmann, Manway Liu, Anupama Reddy, Christian Schnell, Christian Chatenay-Rivauday, Alan Huang, and Christine Fritsch

Abstract

PDF - 92K, NVP-BYL719 does not inhibit mTOR and PIKKs involved in DNA damage-repair processes. A. TSC1 -/- MEFs cells were grown in a 96-well format and treated for 1 h with increased concentrations of RAD001 or NVP-BYL719 (from 0.5 nmol/L to 10 ?mol/L in 1 third dilution steps) and immediately fixed. S235/236P-RPS6 levels were measured and IC50 determined with the Excel module XLfit. Background (no primary Ab incubated); BL, Baseline. B: TSC1 -/- MEFs cells were treated with increasing concentrations of NVP-BYL719 as indicated or RAD001 at 500 nmol/L or an equivalent DMSO concentration for 30 minutes. Levels of S235/236P-RPS6 and total RPS6 in protein- normalized lysates were detected by Western blot analyzis using an activation-state specific antibody, followed by incubation with species- specific HRP-labeled secondary antibody and signal development by ECL. C: 24 h post seeding, A549 cells were treated at the same time with Actinomycin D (Act D) at a concentration of 5 ?mol/L (an agent used to induce DNA damage), and with increasing concentrations of NVP-BYL719 as indicated or with the vehicle control (DMSO) for 1 h. Levels of S15P-p53 and tubulin in protein-normalized lysates were detected by Western blot analysis using an activation-state specific antibody, followed by incubation with species- specific HRP-labeled secondary antibody and signal development by ECL. D: 24 h post seeding, U2OS cells were pre-treated for 1 h with increased concentrations of NVP-BYL719 or KU55933 a specific small molecular mass inhibitor of ATM (Supplementary reference 1) at a concentration of 10 ?mol/L or with the vehicle control (DMSO). The cells were then irradiated with 15 Gy and re-incubated at 37 degrees C for 1 h and then lysed. Levels of S1981P-ATM in protein- normalized lysates were detected by Western blot analysis using an activation-state specific antibody, followed by incubation with species- specific HRP-labeled secondary antibody and signal development by ECL.

Published
2023

33. Supplementary Figure 1 from Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Author

William R. Sellers, Francesco Hofmann, Giorgio Caravatti, Robert Schlegel, Joseph Lehar, Robert Cozens, Marion Wiesmann, Patrick Chene, Carlos Garcia-Echeverria, Markus Boehm, Christopher Wilson, Sauveur-Michel Maira, Saskia M. Brachmann, Joerg Trappe, Youzhen Wang, Stephane Ferretti, Hui Gao, Pascal Furet, Alain De Pover, Dirk Erdmann, Daniel Guthy, Audrey Kauffmann, Manway Liu, Anupama Reddy, Christian Schnell, Christian Chatenay-Rivauday, Alan Huang, and Christine Fritsch

Abstract

PDF - 37K, NVP-BYL719 was tested at 10 different concentrations (from 0.5 nmol/L to 10 μmol/L in 1 third dilution steps) against CLK2 (A) and LRRK2 (B). SelectScreenTM Kinase Profiling Service uses XLfit from IDBS to determine the IC50 values (IC50 CLK2=621 nmol/L; IC50 LRRK2=3'220 nmol/L). The dose response curve is curve fit to model number 205 (sigmoidal dose-response model).

Published
2023

34. Supplementary Figure 5 from Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

Author

Charles F. Voliva, William R. Sellers, Carlos García-Echeverría, Francesco Hofmann, Robert Schlegel, Christopher J. Wilson, Doriano Fabbro, Georg Martiny-Baron, Daniel Menezes, Alain De Pover, Kevin Shoemaker, Patrick Chène, Marion Dorsch, Christine Fritsch, Saskia Brachmann, Marion Wiesmann, Tobi Nagel, Daniel Guthy, Christian Schnell, Dario Sterker, Mark Knapp, Matthew Burger, Alan Huang, Sabina Pecchi, and Sauveur-Michel Maira

Abstract

PDF file - 532K

Published
2023

35. Supplementary Data from Potent and Selective Inhibition of Polycythemia by the Quinoxaline JAK2 Inhibitor NVP-BSK805

Author

Baffert, Fabienne, primary, Régnier, Catherine H., primary, De Pover, Alain, primary, Pissot-Soldermann, Carole, primary, Tavares, Gisele A., primary, Blasco, Francesca, primary, Brueggen, Josef, primary, Chène, Patrick, primary, Drueckes, Peter, primary, Erdmann, Dirk, primary, Furet, Pascal, primary, Gerspacher, Marc, primary, Lang, Marc, primary, Ledieu, David, primary, Nolan, Lynda, primary, Ruetz, Stephan, primary, Trappe, Joerg, primary, Vangrevelinghe, Eric, primary, Wartmann, Markus, primary, Wyder, Lorenza, primary, Hofmann, Francesco, primary, and Radimerski, Thomas, primary

Published
2023
Full Text
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36. Supplementary Material from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity

Author

Maira, Sauveur-Michel, primary, Stauffer, Frédéric, primary, Brueggen, Josef, primary, Furet, Pascal, primary, Schnell, Christian, primary, Fritsch, Christine, primary, Brachmann, Saskia, primary, Chène, Patrick, primary, De Pover, Alain, primary, Schoemaker, Kevin, primary, Fabbro, Doriano, primary, Gabriel, Daniela, primary, Simonen, Marjo, primary, Murphy, Leon, primary, Finan, Peter, primary, Sellers, William, primary, and García-Echeverría, Carlos, primary

Published
2023
Full Text
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37. Supplementary Fig from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity

Author

Maira, Sauveur-Michel, primary, Stauffer, Frédéric, primary, Brueggen, Josef, primary, Furet, Pascal, primary, Schnell, Christian, primary, Fritsch, Christine, primary, Brachmann, Saskia, primary, Chène, Patrick, primary, De Pover, Alain, primary, Schoemaker, Kevin, primary, Fabbro, Doriano, primary, Gabriel, Daniela, primary, Simonen, Marjo, primary, Murphy, Leon, primary, Finan, Peter, primary, Sellers, William, primary, and García-Echeverría, Carlos, primary

Published
2023
Full Text
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38. Supplementary Fig from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity

Author

Carlos García-Echeverría, William Sellers, Peter Finan, Leon Murphy, Marjo Simonen, Daniela Gabriel, Doriano Fabbro, Kevin Schoemaker, Alain De Pover, Patrick Chène, Saskia Brachmann, Christine Fritsch, Christian Schnell, Pascal Furet, Josef Brueggen, Frédéric Stauffer, and Sauveur-Michel Maira

Abstract

Supplementary Fig from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity

Published
2023

39. Supplementary Material from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity

Author

Carlos García-Echeverría, William Sellers, Peter Finan, Leon Murphy, Marjo Simonen, Daniela Gabriel, Doriano Fabbro, Kevin Schoemaker, Alain De Pover, Patrick Chène, Saskia Brachmann, Christine Fritsch, Christian Schnell, Pascal Furet, Josef Brueggen, Frédéric Stauffer, and Sauveur-Michel Maira

Abstract

Supplementary Material from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity

Published
2023

40. Data from Potent and Selective Inhibition of Polycythemia by the Quinoxaline JAK2 Inhibitor NVP-BSK805

Author

Thomas Radimerski, Francesco Hofmann, Lorenza Wyder, Markus Wartmann, Eric Vangrevelinghe, Joerg Trappe, Stephan Ruetz, Lynda Nolan, David Ledieu, Marc Lang, Marc Gerspacher, Pascal Furet, Dirk Erdmann, Peter Drueckes, Patrick Chène, Josef Brueggen, Francesca Blasco, Gisele A. Tavares, Carole Pissot-Soldermann, Alain De Pover, Catherine H. Régnier, and Fabienne Baffert

Abstract

The recent discovery of an acquired activating point mutation in JAK2, substituting valine at amino acid position 617 for phenylalanine, has greatly improved our understanding of the molecular mechanism underlying chronic myeloproliferative neoplasms. Strikingly, the JAK2V617F mutation is found in nearly all patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia and primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative neoplasms and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2V617F and JAK2 wild-type enzymes by a novel substituted quinoxaline, NVP-BSK805, which acts in an ATP-competitive manner. Within the JAK family, NVP-BSK805 displays more than 20-fold selectivity towards JAK2 in vitro, as well as excellent selectivity in broader kinase profiling. The compound blunts constitutive STAT5 phosphorylation in JAK2V617F-bearing cells, with concomitant suppression of cell proliferation and induction of apoptosis. In vivo, NVP-BSK805 exhibited good oral bioavailability and a long half-life. The inhibitor was efficacious in suppressing leukemic cell spreading and splenomegaly in a Ba/F3 JAK2V617F cell-driven mouse mechanistic model. Furthermore, NVP-BSK805 potently suppressed recombinant human erythropoietin-induced polycythemia and extramedullary erythropoiesis in mice and rats. Mol Cancer Ther; 9(7); 1945–55. ©2010 AACR.

Published
2023

41. Data from Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity

Author

Carlos García-Echeverría, William Sellers, Peter Finan, Leon Murphy, Marjo Simonen, Daniela Gabriel, Doriano Fabbro, Kevin Schoemaker, Alain De Pover, Patrick Chène, Saskia Brachmann, Christine Fritsch, Christian Schnell, Pascal Furet, Josef Brueggen, Frédéric Stauffer, and Sauveur-Michel Maira

Abstract

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 is an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G1 arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. Thus, the compound was well tolerated, displayed disease stasis when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies. Ex vivo pharmacokinetic/pharmacodynamic analyses of tumor tissues showed a time-dependent correlation between compound concentration and PI3K/Akt pathway inhibition. Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials. [Mol Cancer Ther 2008;7(7):1–13 [Mol Cancer Ther 2008;7(7):1851–13]

Published
2023

42. Supplementary Data from Potent and Selective Inhibition of Polycythemia by the Quinoxaline JAK2 Inhibitor NVP-BSK805

Author

Thomas Radimerski, Francesco Hofmann, Lorenza Wyder, Markus Wartmann, Eric Vangrevelinghe, Joerg Trappe, Stephan Ruetz, Lynda Nolan, David Ledieu, Marc Lang, Marc Gerspacher, Pascal Furet, Dirk Erdmann, Peter Drueckes, Patrick Chène, Josef Brueggen, Francesca Blasco, Gisele A. Tavares, Carole Pissot-Soldermann, Alain De Pover, Catherine H. Régnier, and Fabienne Baffert

Abstract

Supplementary Data from Potent and Selective Inhibition of Polycythemia by the Quinoxaline JAK2 Inhibitor NVP-BSK805

Published
2023

44. Effects of intestinal fatty acid-binding protein overexpression on fatty acid metabolism in Caco-2 cells

Author

Christian Darimont, Nathalie Gradoux, Elke Persohn, Frédéric Cumin, and Alain De Pover

Subjects
transfection, human enterocytes, cell proliferation, cell differentiation, enterocyte morphology, phospholipids, Biochemistry, QD415-436
Abstract

Intestinal fatty acid-binding protein (I-FABP) is a cytosolic protein expressed at high levels (up to 2% of cytosolic proteins) in the small intestine epithelium. Despite cell transfection studies, its function is still unclear. Indeed, different effects on fatty acid metabolism depending on the cell type and the amount of I-FABP expressed have been reported. Furthermore, a decrease in fatty acid incorporation has been unexpectedly obtained when I-FABP reached 0.72% of cytosolic proteins in fibroblasts (Prows et al. 1997. Arch. Biochem. Biophys. 340: 135). In the present study, the effect of a high level of I-FABP similar to amounts present in the small intestine was investigated in the human colon adenocarcinoma cell line, Caco-2. After transfection with human I-FABP cDNA, a clone expressing 1.5% I-FABP and unchanged level of liver FABP was selected. These cells, which had a lower rate of proliferation as compared with mock-transfected cells, developed the typical morphological characteristics of differentiated enterocytes. Incubation of differentiated cells with [14C]palmitate showed a 34% reduction (P < 0.01) of fatty acid incorporation, whereas the relative distribution of radiolabel into triglycerides was not affected. A nonsignificant 21% reduction of fatty acid incorporation was observed with another clone expressing 10-fold less I-FABP. In conclusion, a high level of I-FABP expressed in a differentiated enterocyte model inhibited fatty acid incorporation, by a mechanism which remains to be defined. —Darimont, C., N. Gradoux, E. Persohn, F. Cumin, and A. De Pover. Effects of intestinal fatty acid-binding protein overexpression on fatty acid metabolism in Caco-2 cells.

Published
2000
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46. Epidermal growth factor regulates fatty acid uptake and metabolism in Caco-2 cells

Author

Darimont, Christian, Gradoux, Nathalie, and De Pover, Alain

Subjects
Epidermal growth factor -- Physiological aspects, Fatty acids -- Research, Ligases -- Physiological aspects, Inflammatory bowel diseases -- Physiological aspects, Biological sciences
Abstract

The effects of epidermal growth factor (EGF) on fatty acid uptake and esterification in a human enterocyte cell line (Caco-2) was studied. EGF was found to inhibit cell uptake of (14C)palmitate and substantially reduce its incorporation into triglycerides. On the other hand, the incorporation in phospholipids was heightened. It was also observed that EGF inhibits palmitate uptake by decreasing the intestinal fatty acid-binding protein level and shifts its use from triglycerides to phospholipids by inhibiting diacylglycerol acyltransferase.

Published
1999

48. Doing business in Belgium.

Author

de Pover, Marie-France and Gorham, Thomas

Subjects
Foreign investments -- Laws, regulations and rules, Belgium -- International trade
Published
1993

49. Study of the Selectivity of Insulin-Like Growth Factor-1 Receptor (IGF1R) Inhibitors

Author

Jean-Christophe Hau, Alain De Pover, Dirk Erdmann, Patrick Chène, Patricia Fontana, Jacqueline Bohn, Catherine Zimmermann, and Anke Blechschmidt

Subjects
biology, Chemistry, medicine.medical_treatment, Isothermal titration calorimetry, Context (language use), body regions, Insulin-like growth factor, Insulin receptor, Mechanism of action, Biochemistry, medicine, biology.protein, medicine.symptom, Receptor, Tyrosine kinase, Insulin-like growth factor 1 receptor
Abstract

The insulin-like growth factor-1 receptor (IGF1R) is a drug target for oncology, and many studies are ongoing to identify compounds that inhibit its tyrosine kinase activity. IGF1R is highly homologous to the insulin receptor (IR) and IGF1R inhibition might be beneficial for patients, while IR inhibition may lead to limiting toxicity. Therefore selectivity for IGF1R over IR is the aim for drug design in this context. A few compounds that selectively inhibit IGF1R over IR in cells have been identified, but none of them show the same levels of selectivity in enzymatic assays. To deter- mine whether this discrepancy is linked to the conditions used in the enzymatic assays, we have studied the interaction be- tween known IGF1R inhibitors (NVP-AEW541, OSI906, AG538, NVP-TAE226) and phosphorylated/unphosphorylated IGF1R/IR proteins with both biophysical (isothermal calorimetry and surface plasmon resonance) and enzymatic methods. In this report, we describe the results of this study and comment on the different degrees of selectivity IGF1R versus IR measured in biochemical and cellular assays. Finally, our study provides new information on the biochemical and mechanism of action of these small molecular weight IGF1R inhibitors.

Published
2014

50. Tetra-substituted imidazoles as a new class of inhibitors of the p53–MDM2 interaction

Author

Andrea, Vaupel, Guido, Bold, Alain, De Pover, Thérèse, Stachyra-Valat, Joanna Hergovich, Lisztwan, Joanna, Hergovich-Lisztwan, Joerg, Kallen, Keiichi, Masuya, and Pascal, Furet

Subjects
Models, Molecular, Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, Antineoplastic Agents, Biochemistry, Non peptide, P53 mdm2, chemistry.chemical_compound, Cell Line, Tumor, Neoplasms, Drug Discovery, Humans, Potency, Imidazole, Protein Interaction Maps, Molecular Biology, Cell Proliferation, biology, Chemistry, Organic Chemistry, Imidazoles, Assay, Proto-Oncogene Proteins c-mdm2, biology.organism_classification, Molecular Medicine, Tetra, Oncology drug, Tumor Suppressor Protein p53
Abstract

Capitalizing on crystal structure information obtained from a previous effort in the search for non peptide inhibitors of the p53–MDM2 interaction, we have discovered another new class of compounds able to disrupt this protein–protein interaction, an important target in oncology drug research. The new inhibitors, based on a tetra-substituted imidazole scaffold, have been optimized to low nanomolar potency in a biochemical assay following a structure-guided approach. An appropriate strategy has allowed us to translate the high biochemical potency in significant anti-proliferative activity on a p53-dependent MDM2 amplified cell line.

Published
2014

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