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Your search keyword '"Iacob, Roxana E."' showing total 168 results
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168 results on '"Iacob, Roxana E."'

3. Recommendations for performing, interpreting and reporting hydrogen deuterium exchange mass spectrometry (HDX-MS) experiments

Author

Masson, Glenn R., Burke, John E., Ahn, Natalie G., Anand, Ganesh S., Borchers, Christoph, Brier, Sébastien, Bou-Assaf, George M., Engen, John R., Englander, S. Walter, Faber, Johan, Garlish, Rachel, Griffin, Patrick R., Gross, Michael L., Guttman, Miklos, Hamuro, Yoshitomo, Heck, Albert J. R., Houde, Damian, Iacob, Roxana E., Jørgensen, Thomas J. D., Kaltashov, Igor A., Klinman, Judith P., Konermann, Lars, Man, Petr, Mayne, Leland, Pascal, Bruce D., Reichmann, Dana, Skehel, Mark, Snijder, Joost, Strutzenberg, Timothy S., Underbakke, Eric S., Wagner, Cornelia, Wales, Thomas E., Walters, Benjamin T., Weis, David D., Wilson, Derek J., Wintrode, Patrick L., Zhang, Zhongqi, Zheng, Jie, Schriemer, David C., and Rand, Kasper D.

Published
2019
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5. Supplementary Table S12 from Tissue-Specific Oncogenic Activity of KRASA146T

Author

Poulin, Emily J., primary, Bera, Asim K., primary, Lu, Jia, primary, Lin, Yi-Jang, primary, Strasser, Samantha Dale, primary, Paulo, Joao A., primary, Huang, Tannie Q., primary, Morales, Carolina, primary, Yan, Wei, primary, Cook, Joshua, primary, Nowak, Jonathan A., primary, Brubaker, Douglas K., primary, Joughin, Brian A., primary, Johnson, Christian W., primary, DeStefanis, Rebecca A., primary, Ghazi, Phaedra C., primary, Gondi, Sudershan, primary, Wales, Thomas E., primary, Iacob, Roxana E., primary, Bogdanova, Lana, primary, Gierut, Jessica J., primary, Li, Yina, primary, Engen, John R., primary, Perez-Mancera, Pedro A., primary, Braun, Benjamin S., primary, Gygi, Steven P., primary, Lauffenburger, Douglas A., primary, Westover, Kenneth D., primary, and Haigis, Kevin M., primary

Published
2023
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6. Supplementary Tables S14-S17 from Tissue-Specific Oncogenic Activity of KRASA146T

Author

Poulin, Emily J., primary, Bera, Asim K., primary, Lu, Jia, primary, Lin, Yi-Jang, primary, Strasser, Samantha Dale, primary, Paulo, Joao A., primary, Huang, Tannie Q., primary, Morales, Carolina, primary, Yan, Wei, primary, Cook, Joshua, primary, Nowak, Jonathan A., primary, Brubaker, Douglas K., primary, Joughin, Brian A., primary, Johnson, Christian W., primary, DeStefanis, Rebecca A., primary, Ghazi, Phaedra C., primary, Gondi, Sudershan, primary, Wales, Thomas E., primary, Iacob, Roxana E., primary, Bogdanova, Lana, primary, Gierut, Jessica J., primary, Li, Yina, primary, Engen, John R., primary, Perez-Mancera, Pedro A., primary, Braun, Benjamin S., primary, Gygi, Steven P., primary, Lauffenburger, Douglas A., primary, Westover, Kenneth D., primary, and Haigis, Kevin M., primary

Published
2023
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7. Data from Tissue-Specific Oncogenic Activity of KRASA146T

Author

Poulin, Emily J., primary, Bera, Asim K., primary, Lu, Jia, primary, Lin, Yi-Jang, primary, Strasser, Samantha Dale, primary, Paulo, Joao A., primary, Huang, Tannie Q., primary, Morales, Carolina, primary, Yan, Wei, primary, Cook, Joshua, primary, Nowak, Jonathan A., primary, Brubaker, Douglas K., primary, Joughin, Brian A., primary, Johnson, Christian W., primary, DeStefanis, Rebecca A., primary, Ghazi, Phaedra C., primary, Gondi, Sudershan, primary, Wales, Thomas E., primary, Iacob, Roxana E., primary, Bogdanova, Lana, primary, Gierut, Jessica J., primary, Li, Yina, primary, Engen, John R., primary, Perez-Mancera, Pedro A., primary, Braun, Benjamin S., primary, Gygi, Steven P., primary, Lauffenburger, Douglas A., primary, Westover, Kenneth D., primary, and Haigis, Kevin M., primary

Published
2023
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8. Supplementary Figures S1-S18 from Tissue-Specific Oncogenic Activity of KRASA146T

Author

Poulin, Emily J., primary, Bera, Asim K., primary, Lu, Jia, primary, Lin, Yi-Jang, primary, Strasser, Samantha Dale, primary, Paulo, Joao A., primary, Huang, Tannie Q., primary, Morales, Carolina, primary, Yan, Wei, primary, Cook, Joshua, primary, Nowak, Jonathan A., primary, Brubaker, Douglas K., primary, Joughin, Brian A., primary, Johnson, Christian W., primary, DeStefanis, Rebecca A., primary, Ghazi, Phaedra C., primary, Gondi, Sudershan, primary, Wales, Thomas E., primary, Iacob, Roxana E., primary, Bogdanova, Lana, primary, Gierut, Jessica J., primary, Li, Yina, primary, Engen, John R., primary, Perez-Mancera, Pedro A., primary, Braun, Benjamin S., primary, Gygi, Steven P., primary, Lauffenburger, Douglas A., primary, Westover, Kenneth D., primary, and Haigis, Kevin M., primary

Published
2023
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9. Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism

Author

Schauer, Nathan J., Liu, Xiaoxi, Magin, Robert S., Doherty, Laura M., Chan, Wai Cheung, Ficarro, Scott B., Hu, Wanyi, Roberts, Rebekka M., Iacob, Roxana E., Stolte, Björn, Giacomelli, Andrew O., Perera, Sumner, McKay, Kyle, Boswell, Sarah A., Weisberg, Ellen L., Ray, Arghya, Chauhan, Dharminder, Dhe-Paganon, Sirano, Anderson, Ken C., Griffin, James D., Li, Jianing, Hahn, William C., Sorger, Peter K., Engen, John R., Stegmaier, Kimberly, Marto, Jarrod A., and Buhrlage, Sara J.

Published
2020
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23. Dynamics of integrin α5β1, fibronectin, and their complex reveal sites of interaction and conformational change.

Author

Yang Su, Iacob, Roxana E., Jing Li, Engen, John R., and Springer, Timothy A.

Subjects
*FIBRONECTINS, *PEPTIDES, *HYDROGEN-deuterium exchange, *INTEGRINS, *CELL adhesion, *BINDING sites, *EXTRACELLULAR matrix
Abstract

Integrin α5β1 mediates cell adhesion to the extracellular matrix by binding fibronectin (Fn). Selectivity for Fn by α5β1 is achieved through recognition of an RGD motif in the 10th type III Fn domain (Fn10) and the synergy site in the ninth type III Fn domain (Fn9). However, details of the interaction dynamics are unknown. Here, we compared synergy-site and Fn-truncation mutations for their α5β1-binding affinities and stabilities. We also interrogated binding of the α5β1 ectodomain headpiece fragment to Fn using hydrogen-deuterium exchange (HDX) mass spectrometry to probe binding sites and sites of integrin conformational change. Our results suggest the synergistic effect of Fn9 requires both specific residues and a folded domain. We found some residues considered important for synergy are required for stability. Additionally, we show decreases in fibronectin HDX are localized to a synergy peptide containing contacting residues in two β-strands, an intervening loop in Fn9, and the RGD-containing loop in Fn10, indicative of binding sites. We also identified binding sites in the α5-subunit β-propeller domain for the Fn9 synergy site and in the β1-subunit βI domain for Fn10 based on decreases in α5β1 HDX. Interestingly, the dominant effect of Fn binding was an increase in α5β1 deuterium exchange distributed over multiple sites that undergo changes in conformation or solvent accessibility and appear to be sites where energy is stored in the higher-energy, open-integrin conformation. Together, our results highlight regions important for α5β1 binding to Fn and dynamics associated with this interaction. [ABSTRACT FROM AUTHOR]

Published
2022
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27. Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors

Author

Zhang, Jianming, Adrián, Francisco J., Jahnke, Wolfgang, Cowan-Jacob, Sandra W., Li, Allen G., Iacob, Roxana E., Sim, Taebo, Powers, John, Dierks, Christine, Sun, Fangxian, Guo, Gui-Rong, Ding, Qiang, Okram, Barun, Choi, Yongmun, Wojciechowski, Amy, Deng, Xianming, Liu, Guoxun, Fendrich, Gabriele, Strauss, André, Vajpai, Navratna, Grzesiek, Stephan, Tuntland, Tove, Liu, Yi, Bursulaya, Badry, Azam, Mohammad, Manley, Paul W., Engen, John R., Daley, George Q., Warmuth, Markus, and Gray, Nathanael S.

Published
2010
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28. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M

Author

Zhou, Wenjun, Ercan, Dalia, Chen, Liang, Yun, Cai-Hong, Li, Danan, Capelletti, Marzia, Cortot, Alexis B., Chirieac, Lucian, Iacob, Roxana E., Padera, Robert, Engen, John R., Wong, Kwok-Kin, Eck, Michael J., Gray, Nathanael S., and Janne, Pasi A.

Subjects
Oncology, Experimental, Erlotinib -- Health aspects, Gefitinib -- Health aspects, Lung cancer, Non-small cell -- Drug therapy, Cancer -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation (1-3). Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR (4,5). All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR. T790M. These agents are 30- to 100-fold more potent against EGFR. T790M, and up to 100-fold less potent against wild-type EGFR., than quinazoline-based EGFR. inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR. T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors., EGFR kinase inhibitors, gefitinib and erlotinib, are effective clinical therapies for NSCLCs that harbour activating mutations in the EGFR kinase domain (1,6). The most common EGFR mutations, L858R. and de1E746_A750, [...]

Published
2009
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29. Conformational disturbance in Abl kinase upon mutation and deregulation

Author

Iacob, Roxana E., Pene-Dumitrescu, Teodora, Zhang, Jianming, Gray, Nathanael S., Smithgall, Thomas E., and Engen, John R.

Subjects
Phosphotransferases -- Genetic aspects, Genetic regulation -- Physiological aspects, Gene mutations -- Physiological aspects, Science and technology
Abstract

Protein dynamics are inextricably linked to protein function but there are few techniques that allow protein dynamics to be conveniently interrogated. For example, mutations and translocations give rise to aberrant proteins such as Bcr-Abl where changes in protein conformation and dynamics are believed to result in deregulated kinase activity that provides the oncogenic signal in chronic myelogeous leukemia. Although crystal structures of the down-regulated c-Abl kinase core have been reported, the conformational impact of mutations that render Abl resistant to smallmolecule kinase inhibitors are largely unknown as is the allosteric interplay of the various regulatory elements of the protein. Hydrogen exchange mass spectrometry (HX MS) was used to compare the conformations of wild-type Abl with a nonmyristoylated form and with 3 clinically relevant imatinib resistance mutants (T3151, Y253H and E255V). A HX-resistant core localized to the interface between the SH2 and kinase domains, a region known to be important for maintaining the down-regulated state. Conformational differences upon demyristoylation were consistent with the SH2 domain moving to the top of the small lobe of the kinase domain as a function of activation. There were conformational changes in the T3151 mutant but, surprisingly, no major changes in conformation were detected in either the Y253H or the E255V mutants. Taken together, these results provide evidence that allosteric interactions and conformational changes play a major role in Abl kinase regulation in solution. Similar analyses could be performed on any protein to provide mechanistic details about conformational changes and protein function. allosteric interactions | chronic mylogenous leukemia | hydrogen exchange | mass spectrometry

Published
2009

30. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

Author

Yu, Wenyu, Chory, Emma J., Wernimont, Amy K., Tempel, Wolfram, Scopton, Alex, Federation, Alexander, Marineau, Jason J., Qi, Jun, Barsyte-Lovejoy, Dalia, Yi, Joanna, Marcellus, Richard, Iacob, Roxana E., Engen, John R., Griffin, Carly, Aman, Ahmed, Wienholds, Erno, Li, Fengling, Pineda, Javier, Estiu, Guillermina, Shatseva, Tatiana, Hajian, Taraneh, Al-awar, Rima, Dick, John E., Vedadi, Masoud, Brown, Peter J., Arrowsmith, Cheryl H., Bradner, James E., and Schapira, Matthieu

Published
2012
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31. Tissue-Specific Oncogenic Activity of KRASA146T

Author

Poulin, Emily J., primary, Bera, Asim K., additional, Lu, Jia, additional, Lin, Yi-Jang, additional, Strasser, Samantha Dale, additional, Paulo, Joao A., additional, Huang, Tannie Q., additional, Morales, Carolina, additional, Yan, Wei, additional, Cook, Joshua, additional, Nowak, Jonathan A., additional, Brubaker, Douglas K., additional, Joughin, Brian A., additional, Johnson, Christian W., additional, DeStefanis, Rebecca A., additional, Ghazi, Phaedra C., additional, Gondi, Sudershan, additional, Wales, Thomas E., additional, Iacob, Roxana E., additional, Bogdanova, Lana, additional, Gierut, Jessica J., additional, Li, Yina, additional, Engen, John R., additional, Perez-Mancera, Pedro A., additional, Braun, Benjamin S., additional, Gygi, Steven P., additional, Lauffenburger, Douglas A., additional, Westover, Kenneth D., additional, and Haigis, Kevin M., additional

Published
2019
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34. Abstract 3354: Chemically induced degradation of the transcription factor BCL6

Author

Kerres, Nina, primary, Steurer, Steffen, additional, Schlager, Stefanie, additional, Bader, Gerd, additional, Caligiuri, Maureen, additional, Dank, Christian, additional, Engen, John R., additional, Ettmayer, Peter, additional, Gerlach, Daniel, additional, Gerstberger, Thomas, additional, Han, Bingsong, additional, Iacob, Roxana E., additional, Kessler, Dirk, additional, Lancia, David R., additional, Moriz, Mayer, additional, Mischerikow, Nikolai, additional, Rumpel, Klaus, additional, Schnitzer, Renate, additional, Voss, Tilman, additional, Zheng, Xiaozhang, additional, Zoephel, Andreas, additional, Kraut, Norbert, additional, McConnell, Darryl, additional, Pearson, Mark, additional, and Koegl, Manfred, additional

Published
2018
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38. Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6

Author

Kerres, Nina, primary, Steurer, Steffen, additional, Schlager, Stefanie, additional, Bader, Gerd, additional, Berger, Helmut, additional, Caligiuri, Maureen, additional, Dank, Christian, additional, Engen, John R., additional, Ettmayer, Peter, additional, Fischerauer, Bernhard, additional, Flotzinger, Gerlinde, additional, Gerlach, Daniel, additional, Gerstberger, Thomas, additional, Gmaschitz, Teresa, additional, Greb, Peter, additional, Han, Bingsong, additional, Heyes, Elizabeth, additional, Iacob, Roxana E., additional, Kessler, Dirk, additional, Kölle, Heike, additional, Lamarre, Lyne, additional, Lancia, David R., additional, Lucas, Simon, additional, Mayer, Moriz, additional, Mayr, Katharina, additional, Mischerikow, Nikolai, additional, Mück, Katja, additional, Peinsipp, Christoph, additional, Petermann, Oliver, additional, Reiser, Ulrich, additional, Rudolph, Dorothea, additional, Rumpel, Klaus, additional, Salomon, Carina, additional, Scharn, Dirk, additional, Schnitzer, Renate, additional, Schrenk, Andreas, additional, Schweifer, Norbert, additional, Thompson, Diane, additional, Traxler, Elisabeth, additional, Varecka, Roland, additional, Voss, Tilman, additional, Weiss-Puxbaum, Alexander, additional, Winkler, Sandra, additional, Zheng, Xiaozhang, additional, Zoephel, Andreas, additional, Kraut, Norbert, additional, McConnell, Darryl, additional, Pearson, Mark, additional, and Koegl, Manfred, additional

Published
2017
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43. Targeting wild-type and T315I Bcr-Abl by combining allosteric with ATP-site inhibitors

Author

Zhang, Jianming, Adrián, Francisco J., Jahnke, Wolfgang, Cowan-Jacob, Sandra W., Li, Allen G., Iacob, Roxana E., Sim, Taebo, Powers, John, Dierks, Christine, Sun, Fangxian, Guo, Gui-Rong, Ding, Qiang, Okram, Barun, Choi, Yongmun, Wojciechowski, Amy, Deng, Xianming, Liu, Guoxun, Fendrich, Gabriele, Strauss, Andre, Vajpai, Navratna, Grzesiek, Stephan, Tuntland, Tove, Liu, Yi, Bursulaya, Badry, Azam, Mohammad, Manley, Paul W., Engen, John R., Daley, George Q., Warmuth, Markus, and Gray, Nathanael S.

Subjects
Male, Models, Molecular, Transplantation, Heterologous, Fusion Proteins, bcr-abl, Antineoplastic Agents, Article, Mass Spectrometry, Piperazines, Inhibitory Concentration 50, Mice, hemic and lymphatic diseases, Cell Line, Tumor, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Antineoplastic Combined Chemotherapy Protocols, Animals, Humans, Bone Marrow Transplantation, Binding Sites, Protein Structure, Tertiary, Disease Models, Animal, Pyrimidines, Drug Resistance, Neoplasm, Benzamides, Mutation, Imatinib Mesylate, Female, Crystallization
Abstract

In an effort to find new pharmacological modalities to overcome resistance to ATP-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry we demonstrate that GNF-2 binds to the myristate binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analog of GNF-2 having improved pharmacokinetic properties, when utilized in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I Bcr-Abl and displayed in vivo efficacy against the recalcitrant T315I Bcr-Abl mutant in a murine bone-marrow transplantation model. These results demonstrate that therapeutically relevant inhibition of Bcr-Abl activity can be achieved using inhibitors that bind to the myristate binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.

Published
2010

47. Correction: Corrigendum: Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

Author

Yu, Wenyu, primary, Chory, Emma J., additional, Wernimont, Amy K., additional, Tempel, Wolfram, additional, Scopton, Alex, additional, Federation, Alexander, additional, Marineau, Jason J., additional, Qi, Jun, additional, Barsyte-Lovejoy, Dalia, additional, Yi, Joanna, additional, Marcellus, Richard, additional, Iacob, Roxana E., additional, Engen, John R., additional, Griffin, Carly, additional, Aman, Ahmed, additional, Wienholds, Erno, additional, Li, Fengling, additional, Pineda, Javier, additional, Estiu, Guillermina, additional, Shatseva, Tatiana, additional, Hajian, Taraneh, additional, Al-awar, Rima, additional, Dick, John E., additional, Vedadi, Masoud, additional, Brown, Peter J., additional, Arrowsmith, Cheryl H., additional, Bradner, James E., additional, and Schapira, Matthieu, additional

Published
2013
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