Unifying Catalysis Framework to Dissect Proteasomal Degradation Paradigms
Open accessAbstract
Diverging from traditional target inhibition, proteasomal protein degradation approaches have emerged as novel therapeutic modalities that embody distinct pharmacological profiles and can access previously undrugged targets. Small molecule degraders have the potential to catalytically destroy target proteins at substoichiometric concentrations, thus lowering administered doses and extending pharmacological effects. With this mechanistic premise, research efforts have advanced the development of small molecule degraders that benefit from stable and increased affinity ternary complexes. However, a holistic framework that evaluates different degradation modes from a catalytic perspective, including focusing on kinetically favored degradation mechanisms, is lacking. In this Outlook, we introduce the concept of an induced cooperativity spectrum as a unifying framework to mechanistically understand catalytic degradation profiles. This framework is bolstered by key examples of published molecular degraders extending from molecular glues to bivalent degraders. Critically, we discuss remaining challenges and future opportunities in drug discovery to rationally design and phenotypically screen for efficient degraders.
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The degree of ternary complex formation may differ from substrate to substrate; a ternary complex that forms too efficiently and remains tightly bound will not lead to efficient degradation.
“the degree of ternary complex formation may differ from substrate to substrate127; that is, a ternary complex that forms too efficiently and remains tightly bound will not lead to efficient degradation.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [127]
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The protein kinase complement of the human genome
Manning, G., Whyte, D. B., Martinez, R., Hunter, T., & Sudarsanam, S. (2002) · Science · doi:10.1126/science.1075762 · Cited by 8,145 · see citing works
Identification of a Primary Target of Thalidomide Teratogenicity
Ito, T., Ando, H., Suzuki, T., Ogura, T., Hotta, K., Imamura, Y., Yamaguchi, Y., & Handa, H. (2010) · Science · doi:10.1126/science.1177319 · Cited by 2,136 · see citing works
The mechanism of action of cyclosporin A and FK506
Schreiber, S. L., & Crabtree, G. R. (1992) · Immunology Today · doi:10.1016/0167-5699(92)90111-j · Cited by 2,127 · see citing works
Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells
Krönke, J., Udeshi, N. D., Narla, A., Grauman, P., Hurst, S. N., McConkey, M., Svinkina, T., Heckl, D., Comer, E., Li, X., et al. (2014) · Science · doi:10.1126/science.1244851 · Cited by 1,879 · see citing works
The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins
Lu, G., Middleton, R. E., Sun, H., Naniong, M., Ott, C. J., Mitsiades, C. S., Wong, K.-K., Bradner, J. E., & Kaelin, W. G. (2014) · Science · doi:10.1126/science.1244917 · Cited by 1,583 · see citing works
Catalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356 · see citing works
Structural basis of PROTAC cooperative recognition for selective protein degradation
Gadd, M. S., Testa, A., Lucas, X., Chan, K.-H., Chen, W., Lamont, D. J., Zengerle, M., & Ciulli, A. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2329 · Cited by 1,242 · see citing works
Lysosome-targeting chimaeras for degradation of extracellular proteins
Banik, S. M., Pedram, K., Wisnovsky, S., Ahn, G., Riley, N. M., & Bertozzi, C. R. (2020) · Nature · doi:10.1038/s41586-020-2545-9 · Cited by 1,199 · see citing works
The dTAG system for immediate and target-specific protein degradation
Nabet, B., Roberts, J. M., Buckley, D. L., Paulk, J., Dastjerdi, S., Yang, A., Leggett, A. L., Erb, M. A., Lawlor, M. A., Souza, A., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0021-8 · Cited by 1,118 · see citing works
Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery
Burslem, G. M., & Crews, C. M. (2020) · Cell · doi:10.1016/j.cell.2019.11.031 · Cited by 1,079 · see citing works
Targeted protein degradation: expanding the toolbox
Schapira, M., Calabrese, M. F., Bullock, A. N., & Crews, C. M. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0047-y · Cited by 960 · see citing works
Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead
Bondeson, D. P., Smith, B. E., Burslem, G. M., Buhimschi, A. D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B. D., Ishchenko, A., & Crews, C. M. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.010 · Cited by 923 · see citing works
Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15
Han, T., Goralski, M., Gaskill, N., Capota, E., Kim, J., Ting, T. C., Xie, Y., Williams, N. S., & Nijhawan, D. (2017) · Science · doi:10.1126/science.aal3755 · Cited by 762 · see citing works
AUTACs: Cargo-Specific Degraders Using Selective Autophagy
Takahashi, D., Moriyama, J., Nakamura, T., Miki, E., Takahashi, E., Sato, A., Akaike, T., Itto-Nakama, K., & Arimoto, H. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.09.009 · Cited by 675 · see citing works
Plasticity in binding confers selectivity in ligand-induced protein degradation
Nowak, R. P., DeAngelo, S. L., Buckley, D., He, Z., Donovan, K. A., An, J., Safaee, N., Jedrychowski, M. P., Ponthier, C. M., Ishoey, M., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0055-y · Cited by 615 · see citing works
Ubiquitylation at the crossroads of development and disease
Rapé, M. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.83 · Cited by 608 · see citing works
Schreiber, S. L. (2021) · Cell · doi:10.1016/j.cell.2020.12.020 · Cited by 598 · see citing works
Allele-selective lowering of mutant HTT protein by HTT–LC3 linker compounds
Li, Z., Wang, C., Wang, Z., Zhu, C., Li, J., Sha, T., Ma, L., Gao, C., Yang, Y., Sun, Y., et al. (2019) · Nature · doi:10.1038/s41586-019-1722-1 · Cited by 551 · see citing works
Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN
Sievers, Q. L., Petzold, G., Bunker, R. D., Renneville, A., Słabicki, M., Liddicoat, B. J., Abdulrahman, W., Mikkelsen, T., Ebert, B. L., & Thomä, N. H. (2018) · Science · doi:10.1126/science.aat0572 · Cited by 537 · see citing works
Donovan, K. A., An, J., Nowak, R. P., Yuan, J. C., Fink, E. C., Berry, B. C., Ebert, B. L., & Fischer, E. S. (2018) · eLife · doi:10.7554/elife.38430 · Cited by 509 · see citing works
Morreale, F. E., & Walden, H. (2016) · Cell · doi:10.1016/j.cell.2016.03.003 · Cited by 495 · see citing works
HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins
Buckley, D. L., Raina, K., Darricarrere, N., Hines, J., Gustafson, J. L., Smith, I. E., Miah, A. H., Harling, J. D., & Crews, C. M. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00442 · Cited by 488 · see citing works
Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16
Zhang, X., Crowley, V. M., Wucherpfennig, T. G., Dix, M. M., & Cravatt, B. F. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0279-5 · Cited by 487 · see citing works
Chemically induced proximity in biology and medicine
Stanton, B. Z., Chory, E. J., & Crabtree, G. R. (2018) · Science · doi:10.1126/science.aao5902 · Cited by 475 · see citing works
A Comprehensive Mathematical Model for Three-Body Binding Equilibria
Douglass, E. F., Miller, C. J., Sparer, G., Shapiro, H., & Spiegel, D. A. (2013) · Journal of the American Chemical Society · doi:10.1021/ja311795d · Cited by 472 · see citing works
A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader
Huang, H.-T., Dobrovolsky, D., Paulk, J., Yang, G., Weisberg, E. L., Doctor, Z. M., Buckley, D. L., Cho, J.-H., Ko, E., Jang, J., et al. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.10.005 · Cited by 437 · see citing works
The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K
Słabicki, M., Kozicka, Z., Petzold, G., Li, Y.-D., Manojkumar, M., Bunker, R. D., Donovan, K. A., Sievers, Q. L., Koeppel, J., Suchyta, D., et al. (2020) · Nature · doi:10.1038/s41586-020-2374-x · Cited by 433 · see citing works
Harnessing the anti-cancer natural product nimbolide for targeted protein degradation
Spradlin, J. N., Hu, X., Ward, C. C., Brittain, S. M., Jones, M. D., Ou, L., To, M., Proudfoot, A., Ornelas, E., Woldegiorgis, M., et al. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0304-8 · Cited by 432 · see citing works
Delineating the role of cooperativity in the design of potent PROTACs for BTK
Zorba, A., Nguyen, C., Xu, Y., Starr, J., Borzilleri, K., Smith, J., Zhu, H., Farley, K. A., Ding, W., Schiemer, J., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1803662115 · Cited by 419 · see citing works
Targeted protein degraders crowd into the clinic
Mullard, A. (2021) · Nature Reviews Drug Discovery · doi:10.1038/d41573-021-00052-4 · Cited by 409 · see citing works
Selective degradation of splicing factor CAPERα by anticancer sulfonamides
Uehara, T., Minoshima, Y., Sagane, K., Sugi, N. H., Mitsuhashi, K. O., Yamamoto, N., Kamiyama, H., Takahashi, K., Kotake, Y., Uesugi, M., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2363 · Cited by 396 · see citing works
SPR-measured dissociation kinetics of PROTAC ternary complexes influence target degradation rate
Roy, M. J., Winkler, S., Hughes, S. J., Whitworth, C., Galant, M., Farnaby, W., Rumpel, K., & Ciulli, A. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00092 · Cited by 386 · see citing works
Systematic analysis of protein turnover in primary cells
Mathieson, T., Franken, H., Kosiński, J., Kurzawa, N., Zinn, N., Sweetman, G. M. A., Poeckel, D., Ratnu, V. S., Schramm, M., Becher, I., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03106-1 · Cited by 384 · see citing works
Rational discovery of molecular glue degraders via scalable chemical profiling
Mayor-Ruiz, C., Bauer, S., Brand, M., Kozicka, Z., Siklos, M., Imrichova, H., Kaltheuner, I. H., Hahn, E., Seiler, K., Koren, A., et al. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0594-x · Cited by 369 · see citing works
The demographics of the ubiquitin system
Clague, M. J., Heride, C., & Urbé, S. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.03.002 · Cited by 365 · see citing works
Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development
Donovan, K. A., Ferguson, F. M., Bushman, J. W., Eleuteri, N. A., Bhunia, D., Ryu, S., Tan, L., Shi, K., Yue, H., Liu, X., et al. (2020) · Cell · doi:10.1016/j.cell.2020.10.038 · Cited by 359 · see citing works
SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrate
Matyskiela, M. E., Couto, S., Zheng, X., Lu, G., Hui, J., Stamp, K., Drew, C., Ren, Y., Wang, M., Carpenter, A., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0129-x · Cited by 338 · see citing works
Ward, C. C., Kleinman, J. I., Brittain, S. M., Lee, P. S., Chung, C. Y. S., Kim, K., Petri, Y., Thomas, J. R., Tallarico, J. A., McKenna, J. M., et al. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.8b01083 · Cited by 336 · see citing works
Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer
Petralia, F., Tignor, N., Reva, B., Koptyra, M., Chowdhury, S., Rykunov, D., Krek, A., Ma, W., Zhu, Y., Ji, J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.10.044 · Cited by 317 · see citing works
Quantitative Live-Cell Kinetic Degradation and Mechanistic Profiling of PROTAC Mode of Action
Riching, K. M., Mahan, S. D., Corona, C. R., McDougall, M. G., Vasta, J. D., Robers, M. B., Urh, M., & Daniels, D. L. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.8b00692 · Cited by 307 · see citing works
Systems biology in cardiovascular disease: a multiomics approach
Joshi, A., Rienks, M., Theofilatos, K., & Mayr, M. (2020) · Nature Reviews Cardiology · doi:10.1038/s41569-020-00477-1 · Cited by 305 · see citing works
Cooperativity and biological complexity
Whitty, A. (2008) · Nature Chemical Biology · doi:10.1038/nchembio0808-435 · Cited by 288 · see citing works
Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models
Silva, M. C., Ferguson, F. M., Cai, Q., Donovan, K. A., Nandi, G., Patnaik, D., Zhang, T., Huang, H.-T., Lucente, D. E., Dickerson, B. C., et al. (2019) · eLife · doi:10.7554/elife.45457 · Cited by 283 · see citing works
Free-Energy Landscape of Enzyme Catalysis
Benkovic, S. J., Hammes, G. G., & Hammes‐Schiffer, S. (2008) · Biochemistry · doi:10.1021/bi800049z · Cited by 282 · see citing works
Flexibility, Diversity, and Cooperativity: Pillars of Enzyme Catalysis
Hammes, G. G., Benkovic, S. J., & Hammes‐Schiffer, S. (2011) · Biochemistry · doi:10.1021/bi201486f · Cited by 275 · see citing works
Small-molecule-induced polymerization triggers degradation of BCL6
Słabicki, M., Yoon, H., Koeppel, J., Nitsch, L., Roy Burman, S. S., Di Genua, C., Donovan, K. A., Sperling, A. S., Hunkeler, M., Tsai, J. M., et al. (2020) · Nature · doi:10.1038/s41586-020-2925-1 · Cited by 270 · see citing works
Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide
Jan, M., Scarfò, I., Larson, R. C., Walker, A., Schmidts, A., Guirguis, A. A., Gasser, J. A., Slabicki, M. M., Bouffard, A. A., Castaño, A. P., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abb6295 · Cited by 270 · see citing works
Multispecific drugs herald a new era of biopharmaceutical innovation
Deshaies, R. J. (2020) · Nature · doi:10.1038/s41586-020-2168-1 · Cited by 262 · see citing works
Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex
Bussiere, D. E., Xie, L., Srinivas, H., Shu, W., Burke, A., Be, C., Zhao, J., Godbole, A., King, D., Karki, R. G., et al. (2020) · Nature Chemical Biology · doi:10.1038/s41589-019-0411-6 · Cited by 257 · see citing works
Hughes, S. J., & Ciulli, A. (2017) · Essays in Biochemistry · doi:10.1042/ebc20170041 · Cited by 240 · see citing works
Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2
Mares, A., Miah, A. H., Smith, I. E. D., Rackham, M., Thawani, A. R., Cryan, J., Haile, P. A., Votta, B. J., Beal, A. M., Capriotti, C., et al. (2020) · Communications Biology · doi:10.1038/s42003-020-0868-6 · Cited by 232 · see citing works
Proteolysis‐targeting chimeras in drug development: A safety perspective
Moreau, K., Coen, M., Zhang, A. X., Pachl, F., Castaldi, M. P., Dahl, G., Boyd, H., Scott, C., & Newham, P. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15014 · Cited by 229 · see citing works
Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction
Simonetta, K. R., Taygerly, J., Boyle, K., Basham, S. E., Padovani, C., Lou, Y., Cummins, T. J., Yung, S. L., von Soly, S. K., Kayser, F., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09358-9 · Cited by 217 · see citing works
Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation
Lv, L., Chen, P., Cao, L., Li, Y., Zeng, Z., Cui, Y., Wu, Q., Li, J., Wang, J.-H., Dong, M.-Q., et al. (2020) · eLife · doi:10.7554/elife.59994 · Cited by 215 · see citing works
Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6
Kerres, N., Steurer, S., Schlager, S., Bader, G., Berger, H., Caligiuri, M., Dank, C., Engen, J. R., Ettmayer, P., Fischerauer, B., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.081 · Cited by 207 · see citing works
Unifying principles of bifunctional, proximity-inducing small molecules
Gerry, C. J., & Schreiber, S. L. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0469-1 · Cited by 199 · see citing works
Phosphorylation-Inducing Chimeric Small Molecules
Siriwardena, S. U., Godage, D. N. P. M., Shoba, V. M., Lai, S., Shi, M., Wu, P., Chaudhary, S. K., Schreiber, S. L., & Choudhary, A. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c05537 · Cited by 196 · see citing works
Targeted protein degradation as a powerful research tool in basic biology and drug target discovery
Wu, T., Yoon, H., Xiong, Y., Dixon-Clarke, S. E., Nowak, R. P., & Fischer, E. S. (2020) · Nature Structural & Molecular Biology · doi:10.1038/s41594-020-0438-0 · Cited by 188 · see citing works
Luo, M., Spradlin, J. N., Boike, L., Tong, B., Brittain, S. M., McKenna, J. M., Tallarico, J. A., Schirle, M., Maimone, T. J., & Nomura, D. K. (2021) · Cell Chemical Biology · doi:10.1016/j.chembiol.2021.01.005 · Cited by 186 · see citing works
Harnessing the Power of Proteolysis for Targeted Protein Inactivation
Verma, R., Mohl, D., & Deshaies, R. J. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.01.010 · Cited by 185 · see citing works
Assessing Different E3 Ligases for Small Molecule Induced Protein Ubiquitination and Degradation
Ottis, P., Toure, M., Cromm, P. M., Ko, E., Gustafson, J. L., & Crews, C. M. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.7b00485 · Cited by 176 · see citing works
Lim, S., Khoo, R., Peh, K. M., Teo, J., Chang, S. C., Ng, S., Beilhartz, G. L., Melnyk, R. A., Johannes, C. W., Brown, C. J., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1920251117 · Cited by 170 · see citing works
Fundamental aspects of DMPK optimization of targeted protein degraders
Cantrill, C., Chaturvedi, P., Rynn, C., Schaffland, J. P., Walter, I., & Wittwer, M. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.03.012 · Cited by 169 · see citing works
Drummond, M. L., Henry, A., Li, H., & Williams, C. I. (2020) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.0c00897 · Cited by 166 · see citing works
Targeted protein degradation: current and future challenges
Hanzl, A., & Winter, G. E. (2020) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2019.11.012 · Cited by 157 · see citing works
Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta
Bai, N., Miller, S. A., Andrianov, G. V., Yates, M., Kirubakaran, P., & Karanicolas, J. (2021) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.0c01451 · Cited by 157 · see citing works
A Biophysical Perspective on Enzyme Catalysis
Agarwal, P. K. (2018) · Biochemistry · doi:10.1021/acs.biochem.8b01004 · Cited by 153 · see citing works
Ottis, P., Palladino, C., Thienger, P., Britschgi, A., Heichinger, C., Berrera, M., Julien-Laferrière, A., Roudnicky, F., Kam‐Thong, T., Bischoff, J. R., et al. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00525 · Cited by 153 · see citing works
Proteasome Activation by Small Molecules
Leestemaker, Y., de Jong, A., Witting, K. F., Penning, R., Schuurman, K. G., Rodenko, B., Zaal, E. A., van de Kooij, B., Laufer, S., Heck, A. J. R., et al. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.05.010 · Cited by 146 · see citing works
Heterobifunctional Molecules Induce Dephosphorylation of Kinases–A Proof of Concept Study
Yamazoe, S., Tom, J., Fu, Y., Wu, W., Zeng, L., Sun, C., Liu, Q., Lin, J. M., Lin, K., Fairbrother, W. J., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01167 · Cited by 145 · see citing works
Smith, S. R., Dupont, C. L., McCarthy, J. K., Broddrick, J. T., Obornı́k, M., Horák, A., Füssy, Z., Cihlář, J., Kleeßen, S., Zheng, H., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12407-y · Cited by 143 · see citing works
McCoull, W., Cheung, T., Anderson, E., Barton, P., Burgess, J., Byth, K., Cao, Q., Castaldi, M. P., Chen, H., Chiarparin, E., et al. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.8b00698 · Cited by 139 · see citing works
Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling
You, I., Erickson, E. C., Donovan, K. A., Eleuteri, N. A., Fischer, E. S., Gray, N. S., & Toker, A. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.11.014 · Cited by 132 · see citing works
Engineering a Proximity-Directed O-GlcNAc Transferase for Selective Protein O-GlcNAcylation in Cells
Ramirez, D. H., Aonbangkhen, C., Wu, H., Naftaly, J. A., Tang, S., O’Meara, T. R., & Woo, C. M. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00074 · Cited by 128 · see citing works
Targeted protein degradation and the enzymology of degraders
Fisher, S. L., & Phillips, A. J. (2018) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2018.05.004 · Cited by 126 · see citing works
Sievers, Q. L., Gasser, J. A., Cowley, G. S., Fischer, E. S., & Ebert, B. L. (2018) · Blood · doi:10.1182/blood-2018-01-821769 · Cited by 124 · see citing works
Shirasaki, R., Matthews, G. M., Gandolfi, S., de Matos Simoes, R., Buckley, D. L., Raja Vora, J., Sievers, Q. L., Brüggenthies, J. B., Dashevsky, O., Poarch, H., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108532 · Cited by 123 · see citing works
Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes
Schiemer, J., Horst, R., Meng, Y., Montgomery, J. I., Xu, Y., Feng, X., Borzilleri, K., Uccello, D. P., Leverett, C., Brown, S., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-020-00686-2 · Cited by 113 · see citing works
TRIP12 promotes small-molecule-induced degradation through K29/K48-branched ubiquitin chains
Kaiho-Soma, A., Akizuki, Y., Igarashi, K., Endo, A., Shoda, T., Kawase, Y., Demizu, Y., Naito, M., Saeki, Y., Tanaka, K., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.01.023 · Cited by 110 · see citing works
Target protein deglycosylation in living cells by a nanobody-fused split O-GlcNAcase
Ge, Y., Ramirez, D. H., Yang, B., D’Souza, A. K., Aonbangkhen, C., Wong, S. M., & Woo, C. M. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00757-y · Cited by 106 · see citing works
Bensimon, A., Pizzagalli, M. D., Kartnig, F., Dvorak, V., Essletzbichler, P., Winter, G. E., & Superti-Furga, G. (2020) · Cell Chemical Biology · doi:10.1016/j.chembiol.2020.04.003 · Cited by 102 · see citing works
Critical Assessment of Targeted Protein Degradation as a Research Tool and Pharmacological Modality
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Bellenie, B. R., Cheung, K.-M. J., Varela, A., Pierrat, O. A., Collie, G. W., Box, G. M., Bright, M. D., Gowan, S., Hayes, A., Rodrigues, M. J., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b02076 · Cited by 74 · see citing works
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- Authors
- Rodriguez-Rivera, F. P., & Levi, S. M.
- Affiliations
- Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
- Pfizer (United States) (US)
- Venue
- ACS Central Science
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-06-16
- Volume
- 7
- Issue
- 7
- Pages
- 1117-1125
- ISSN
- 2374-7943 (ISSN-L)
- 2374-7951
- PMC
- PMC8323112
- OpenAlex
- W3167795530
- Cited by
- 30
- References
- 109
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 3 · 2023: 4 · 2022: 9 · 2021: 1
- FWCI
- 0.45
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- Locations
- ACS Central Science (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Pfizer (S.M.L. is an employee of Pfizer, Inc.)
- Merck (F.P.R.-R. is an employee of Merck & Co., Inc.)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- small-molecule degraders, ternary complex stability, molecular glues, phenotypic screening
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