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Start Over Author "Ishchenko, Alexey" Journal cell chemical biology
2 results on '"Ishchenko, Alexey"'

2. The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study

Author

Cromm, Philipp M., Crews, Craig M., Mainolfi, Nello, Rasmusson, Tim, Poulikakos, Poulikos I., Zhang, Chao, Bollag, Gideon, Shokat, Kevan M., Rosen, Neal, Agianian, Bogos, Gavathiotis, Evripidis, Raina, Kanak, Durrant, David E., Morrison, Deborah K., Neklesa, Taavi K., Winkler, James D., Chang, F., Steelman, L. S., Lee, J. T., Shelton, J. G., Navolanic, P. M., Blalock, W. L., Franklin, R. A., McCubrey, J. A., Burslem, George M., Smith, Blake E., Lai, Ashton C., Jaime-Figueroa, Saul, McQuaid, Daniel C., Bondeson, Daniel P., Toure, Momar, Dong, Hanqing, Qian, Yimin, Wang, Jing, Crew, Andrew P., Hines, John, Sanchez, Jaquelyn N., Wang, Ton, Cohen, Mark S., Shelledy, PharmD, Lindsay, Roman, PharmD, BCOP, Danielle, Davies, Helen, Bignell, Graham R., Cox, Charles, Stephens, Philip, Edkins, Sarah, Clegg, Sheila, Teague, Jon, Woffendin, Hayley, Garnett, Mathew J., Bottomley, William, Davis, Neil, Dicks, Ed, Ewing, Rebecca, Floyd, Yvonne, Gray, Kristian, Hall, Sarah, Hawes, Rachel, Hughes, Jaime, Kosmidou, Vivian, Menzies, Andrew, Mould, Catherine, Parker, Adrian, Stevens, Claire, Watt, Stephen, Hooper, Steven, Jayatilake, Hiran, Gusterson, Barry A., Cooper, Colin, Shipley, Janet, Hargrave, Darren, Pritchard-Jones, Katherine, Maitland, Norman, Chenevix-Trench, Georgia, Riggins, Gregory J., Bigner, Darell D., Palmieri, Giuseppe, Cossu, Antonio, Flanagan, Adrienne, Nicholson, Andrew, Ho, Judy W.C., Leung, Suet Y., Yuen, Siu T., Weber, Barbara L., Seigler, Hilliard F., Darrow, Timothy L., Paterson, Hugh, Wooster, Richard, Stratton, Michael R., Futreal, P. Andrew, Spevak, Wayne, Zhang, Ying, Burton, Elizabeth A., Ma, Yan, Habets, Gaston, Zhang, Jiazhong, Lin, Jack, Ewing, Todd, Matusow, Bernice, Tsang, Garson, Marimuthu, Adhirai, Cho, Hanna, Wu, Guoxian, Wang, Weiru, Fong, Daniel, Nguyen, Hoa, Shi, Songyuan, Womack, Patrick, Nespi, Marika, Shellooe, Rafe, Carias, Heidi, Powell, Ben, Light, Emily, Sanftner, Laura, Walters, Jason, Tsai, James, West, Brian L., Visor, Gary, Rezaei, Hamid, Lin, Paul S., Nolop, Keith, Ibrahim, Prabha N., Hirth, Peter, Arozarena, Imanol, Wellbrock, Claudia, Samatar, Ahmed A., Karoulia, Zoi, Chapman, Paul B., Hauschild, Axel, Robert, Caroline, Haanen, John B., Ascierto, Paolo, Larkin, James, Dummer, Reinhard, Garbe, Claus, Testori, Alessandro, Maio, Michele, Hogg, David, Lorigan, Paul, Lebbe, Celeste, Jouary, Thomas, Schadendorf, Dirk, Ribas, Antoni, O'Day, Steven J., Sosman, Jeffrey A., Kirkwood, John M., Eggermont, Alexander M.M., Dreno, Brigitte, Li, Jiang, Nelson, Betty, Hou, Jeannie, Lee, Richard J., Flaherty, Keith T., McArthur, Grant A., Vogelstein, Bert, Papadopoulos, Nickolas, Velculescu, Victor E., Zhou, Shibin, Diaz, Luis A., Kinzler, Kenneth W., Millington, G. W.M., Buhimschi, Alexandru D., Hamman, Brian D., and Ishchenko, Alexey

Subjects
0301 basic medicine, Small molecular weight membrane-permeable inhibito, MAPK/p38, selective degradation, Raf kinases, Clinical Biochemistry, Receptor Protein-Tyrosine Kinases, protein-protein interactions, Signal transduction, Ligands, ERK cascade, protein dimerisation, Biochemistry, ternary complex, Receptor tyrosine kinase, Therapeutic intervention, 0302 clinical medicine, PROTACs, Drug Discovery, Kinome, Enzyme Inhibitors, Cereblon, E3 ligase, SNIPER, receptor tyrosine kinases, Manchester Cancer Research Centre, biology, Ras pathway, targeted degradation, Ubiquitin ligase, Raf inhibitors, 030220 oncology & carcinogenesis, Cytokines, cancer therapy, Molecular Medicine, Protein family, Ubiquitin-Protein Ligases, EGFR, hydrophobic tagging, Undruggable proteome, chemical biology, Protein degradation, Article, PROTAC, 03 medical and health sciences, proteomics, HER2, VHL, Humans, Molecular Biology, c-Met, Pharmacology, Heterobifunctional degrader, ResearchInstitutes_Networks_Beacons/mcrc, Proteolysis targeting chimera, Ubiquitination, Oncogenes, 030104 developmental biology, MAPK kinase cascade, CRBN, Proteolysis, biology.protein, Targeted protein degradation
Abstract

Proteolysis targeting chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of endogenous proteins. Herein we describe the development of PROTACs for receptor tyrosine kinases, a protein family yet to be targeted for induced protein degradation. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone: direct comparisons of fully functional, target-degrading PROTACs with target-inhibiting variants that contain an inactivated E3 ligase-recruiting ligand show that degradation leads to more potent inhibition of cell proliferation and a more durable and sustained downstream signaling response, and thus addresses the kinome rewiring challenge seen with many receptor tyrosine kinase inhibitors. Combined, these findings demonstrate the ability to target receptor tyrosine kinases for degradation using the PROTAC technology and outline the advantages of this degradation-based approach. Burslem, Smith et al. describe the development of PROTACs capable of degrading transmembrane receptor tyrosine kinases and further highlight the advantages of degradation over inhibition in terms of potency, duration of effect, and combating compensatory signaling.

Published
2018

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