Cited by 534Protein Degradation and InhibitorsChemical Synthesis and AnalysisUbiquitin and proteasome pathways

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Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?

Churcher, Ian·2018·Journal of Medicinal Chemistry

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Abstract

Targeted protein degradation, using bifunctional small molecules (Protacs) to remove specific proteins from within cells, has emerged as a novel drug discovery strategy with the potential to offer therapeutic interventions not achievable with existing approaches. In this Perspective, the brief history of the field is surveyed from a drug discovery perspective with a focus on the key advances in knowledge which have led to the definition and exemplification of protein degradation concepts and their resulting applications to medicine discovery. The approach has the potential to bring disruptive change to drug discovery; the many potential advantages and outstanding challenges which lie ahead of this technology are discussed.

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Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1
Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(00)00129-0 · Cited by 18,139
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (1997) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(96)00423-1 · Cited by 11,484
Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566
Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation
Sakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141230798 · Cited by 2,609
Breaking the chains: structure and function of the deubiquitinases
Komander, D., Clague, M. J., & Urbé, S. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2731 · Cited by 1,969
Phthalimide conjugation as a strategy for in vivo target protein degradation
Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760
Small-molecule inhibitors of protein–protein interactions: progressing towards the dream
Arkin, M. R., & Wells, J. A. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1343 · Cited by 1,705
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486
THE UBIQUITIN SYSTEM FOR PROTEIN DEGRADATION
Hershko, A., & Ciechanover, A. J. (1992) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.61.070192.003553 · Cited by 1,448
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
Self-citation
Factors affecting therapeutic compliance: A review from the patient’s perspective
Li, S.-C. (2008) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s1458 · Cited by 1,290
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
Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide
Fischer, E. S., Böhm, K., Lydeard, J. R., Yang, H., Stadler, M. B., Cavadini, S., Nagel, J., Serluca, F., Acker, V., Lingaraju, G. M., et al. (2014) · Nature · doi:10.1038/nature13527 · Cited by 1,141
Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., Hines, J., Winkler, J. D., Crew, A. P., Coleman, K., et al. (2015) · Chemistry & Biology · doi:10.1016/j.chembiol.2015.05.009 · Cited by 1,140
Proteolysis: from the lysosome to ubiquitin and the proteasome
Ciechanover, A. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1552 · Cited by 1,133
Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4
Zengerle, M., Chan, K.-H., & Ciulli, A. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00216 · Cited by 1,056
Applications of CRISPR technologies in research and beyond
Barrangou, R., & Doudna, J. A. (2016) · Nature Biotechnology · doi:10.1038/nbt.3659 · Cited by 1,005
The logic of the 26S proteasome.
Collins, G. A., & Goldberg, A. L. (2017) · Cell · doi:10.1016/j.cell.2017.04.023 · Cited by 933
The delivery of therapeutic oligonucleotides
Juliano, R. L. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw236 · Cited by 882
Genome-Wide and Functional Annotation of Human E3 Ubiquitin Ligases Identifies MULAN, a Mitochondrial E3 that Regulates the Organelle's Dynamics and Signaling
Li, W., Bengtson, M. H., Ulbrich, A., Matsuda, A., Reddy, V. A., Orth, A. P., Chanda, S. K., Batalov, S., & Joazeiro, C. A. P. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001487 · Cited by 875
PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer
Raina, K., Lu, J., Qian, Y., Altieri, M., Gordon, D., Rossi, A. M. K., Wang, J., Chen, X., Dong, H., Siu, K., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521738113 · Cited by 852
Getting Across the Cell Membrane: An Overview for Small Molecules, Peptides, and Proteins
Yang, N. J., & Hinner, M. J. (2015) · Methods in Molecular Biology · doi:10.1007/978-1-4939-2272-7_3 · Cited by 826
The emerging complexity of protein ubiquitination
Komander, D. (2009) · Biochemical Society Transactions · doi:10.1042/bst0370937 · Cited by 821
Polar Molecular Surface as a Dominating Determinant for Oral Absorption and Brain Penetration of Drugs
Kelder, J., Grootenhuis, P. D. J., Bayada, D. M., Delbressine, L. P. C., & Ploemen, J.-P. H. T. M. (1999) · Pharmaceutical Research · doi:10.1023/a:1015040217741 · Cited by 819
Small‐Molecule PROTACS: New Approaches to Protein Degradation
Toure, M., & Crews, C. M. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201507978 · Cited by 674
Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics
Schneekloth, A. R., Pucheault, M., Tae, H. S., & Crews, C. M. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.07.114 · Cited by 635
Modular PROTAC design for the degradation of oncogenic BCR-ABL
Lai, A. C., Toure, M., Hellerschmied, D., Salami, J., Jaime‐Figueroa, S., Ko, E., Hines, J., & Crews, C. M. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201507634 · Cited by 618
Targeted protein degradation by PROTACs
Neklesa, T. K., Winkler, J. D., & Crews, C. M. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.027 · Cited by 599
Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction
Buckley, D. L., Van Molle, I., Gareiss, P. C., Tae, H. S., Michel, J., Noblin, D. J., Jorgensen, W. L., Ciulli, A., & Crews, C. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja209924v · Cited by 569
Ubiquitin-like protein conjugation and the ubiquitin–proteasome system as drug targets
Bedford, L., Lowe, J., Dick, L. R., Mayer, R. J., & Brownell, J. E. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3321 · Cited by 563
Proteasome Inhibitors: An Expanding Army Attacking a Unique Target
Kisselev, A. F., van der Linden, W. A., & Overkleeft, H. S. (2012) · Chemistry & Biology · doi:10.1016/j.chembiol.2012.01.003 · Cited by 542
Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs
Chamberlain, P. P., Lopez-Girona, A., Miller, K., Carmel, G., Pagarigan, B., Chie-Leon, B., Rychak, E., Corral, L. G., Ren, Y. J., Wang, M., et al. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2874 · Cited by 531
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
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
Perilous journey: a tour of the ubiquitin–proteasome system
Kleiger, G., & Mayor, T. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2013.12.003 · Cited by 431
Targeted Protein Degradation: from Chemical Biology to Drug Discovery
Cromm, P. M., & Crews, C. M. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.05.024 · Cited by 428
Development of Protacs to Target Cancer-promoting Proteins for Ubiquitination and Degradation
Sakamoto, K. M., Kim, K. B., Verma, R., Ransick, A., Stein, B., Crews, C. M., & Deshaies, R. J. (2003) · Molecular & Cellular Proteomics · doi:10.1074/mcp.t300009-mcp200 · Cited by 425
Structure-Guided Design and Optimization of Small Molecules Targeting the Protein–Protein Interaction between the von Hippel–Lindau (VHL) E3 Ubiquitin Ligase and the Hypoxia Inducible Factor (HIF) Alpha Subunit with in Vitro Nanomolar Affinities
Galdeano, C., Gadd, M. S., Soares, P., Scaffidi, S., Molle, I. V., Birced, I., Hewitt, S. H., Dias, D. M. G., & Ciulli, A. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm5011258 · Cited by 424
Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting Chimeras
Lebraud, H., Wright, D. J., Johnson, C. N., & Heightman, T. D. (2016) · ACS Central Science · doi:10.1021/acscentsci.6b00280 · Cited by 413
Global analysis of cellular protein translation by pulsed SILAC
Schwanhäusser, B., Gossen, M., Dittmar, G., & Selbach, M. (2009) · PROTEOMICS · doi:10.1002/pmic.200800275 · Cited by 356
The predator becomes the prey: regulating the ubiquitin system by ubiquitylation and degradation
Weissman, A. M., Shabek, N., & Ciechanover, A. J. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3173 · Cited by 326
Going further than Lipinski's rule in drug design
Walters, W. P. (2012) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2012.648612 · Cited by 322
Small‐Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1α
Buckley, D. L., Gustafson, J. L., Van Molle, I., Roth, A. G., Tae, H. S., Gareiss, P. C., Jorgensen, W. L., Ciulli, A., & Crews, C. M. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201206231 · Cited by 302
Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands
Remillard, D., Buckley, D. L., Paulk, J., Brien, G. L., Sonnett, M., Seo, H., Dastjerdi, S., Wühr, M., Dhe‐Paganon, S., Armstrong, S. A., et al. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201611281 · Cited by 292
Will the Ubiquitin System Furnish as Many Drug Targets as Protein Kinases?
Cohen, P., & Tcherpakov, M. (2010) · Cell · doi:10.1016/j.cell.2010.11.016 · Cited by 280
In Vivo Knockdown of Pathogenic Proteins via Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERs)
Ohoka, N., Okuhira, K., Ito, M., Nagai, K., Shibata, N., Hattori, T., Ujikawa, O., Shimokawa, K., Sano, O., Koyama, R., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.768853 · Cited by 240
Dissecting Fragment-Based Lead Discovery at the von Hippel-Lindau Protein:Hypoxia Inducible Factor 1α Protein-Protein Interface
Molle, I. V., Thomann, A., Buckley, D. L., So, E. C., Lang, S., Crews, C. M., & Ciulli, A. (2012) · Chemistry & Biology · doi:10.1016/j.chembiol.2012.08.015 · Cited by 203
Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells
Saenz, D. T., Fiskus, W. C., Qian, Y., Manshouri, T., Rajapakshe, K., Raina, K., Coleman, K. G., Crew, A. P. A., Shen, A., Mill, C. P., et al. (2017) · Leukemia · doi:10.1038/leu.2016.393 · Cited by 187
Pharmaceutical Amorphous Nanoparticles
Jog, R., & Burgess, D. J. (2016) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2016.09.014 · Cited by 186
Oral Selective Estrogen Receptor Downregulators (SERDs), a Breakthrough Endocrine Therapy for Breast Cancer
McDonnell, D. P., Wardell, S. E., & Norris, J. D. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00760 · Cited by 178
Development of BCR-ABL degradation inducers via the conjugation of an imatinib derivative and a cIAP1 ligand
Demizu, Y., Shibata, N., Hattori, T., Ohoka, N., Motoi, H., Misawa, T., Shoda, T., Naito, M., & Kurihara, M. (2016) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2016.09.041 · Cited by 125
Localization to the Proteasome Is Sufficient for Degradation
Janse, D. M., Crosas, B., Finley, D. J., & Church, G. M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402954200 · Cited by 121
Targeted protein knockdown using small molecule degraders
Raina, K., & Crews, C. M. (2017) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2017.05.016 · Cited by 113
Oligonucleotide Therapeutics: Chemistry, Delivery and Clinical Progress
Sharma, V. K., & Watts, J. K. (2015) · Future Medicinal Chemistry · doi:10.4155/fmc.15.144 · Cited by 112
Rad23 escapes degradation because it lacks a proteasome initiation region
Fishbain, S., Prakash, S., Herrig, A., Elsasser, S., & Matouschek, A. T. (2011) · Nature Communications · doi:10.1038/ncomms1194 · Cited by 101
GABAA Receptor Subtype-Selective Modulators. II. α5-Selective Inverse Agonists for Cognition Enhancement
Atack, J. R. (2011) · Current Topics in Medicinal Chemistry · doi:10.2174/156802611795371314 · Cited by 85
Ubiquitin‐like domains can target to the proteasome but proteolysis requires a disordered region
Yu, H., Kago, G., Yellman, C. M., & Matouschek, A. T. (2016) · The EMBO Journal · doi:10.15252/embj.201593147 · Cited by 71
The Lysine48‐Based Polyubiquitin Chain Proteasomal Signal: Not a Single Child Anymore
Kravtsova‐Ivantsiv, Y., Sommer, T., & Ciechanover, A. J. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201205656 · Cited by 68
The Receptor Concept: A Continuing Evolution
Limbird, L. E. (2004) · Molecular Interventions · doi:10.1124/mi.4.6.6 · Cited by 61
Redirecting the specificity of ubiquitination by modifying ubiquitin-conjugating enzymes.
Gosink, M. M., & Vierstra, R. D. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9117 · Cited by 53
Small molecule-mediated protein knockdown as a new approach to drug discovery
Tinworth, C. P., Lithgow, H., & Churcher, I. (2016) · MedChemComm · doi:10.1039/c6md00347h · Cited by 32
Self-citation
Characterization of a New Class of Androgen Receptor Antagonists with Potential Therapeutic Application in Advanced Prostate Cancer
Li, H., Hassona, M. D. H., Lack, N. A., Axerio-Cilies, P., Leblanc, E., Tavassoli, P., Kanaan, N., Frewin, K., Singh, K., Adomat, H. H., et al. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0267 · Cited by 28
Evaluation of a Diffusion-Driven Mechanism for Substrate Ubiquitination by the SCF-Cdc34 Ubiquitin Ligase Complex
Petroski, M. D., Kleiger, G., & Deshaies, R. J. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.10.010 · Cited by 21
Emerging Methods in Chemoproteomics with Relevance to Drug Discovery
Nguyen, C., West, G. M., & Geoghegan, K. F. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-6539-7_2 · Cited by 21
Regulation of Proteasomal Degradation by Modulating Proteasomal Initiation Regions
Takahashi, K., Matouschek, A., & Inobe, T. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00554 · Cited by 13
Trial of thalidomide in insomnia associated with the third trimester
NULSEN, R. O. (1961) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(15)33360-3 · Cited by 5

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Pettersson, M., & Crews, C. M. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2019.01.002 · Cited by 830
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Sun, X., Gao, H., Yang, Y., He, M., Wu, Y., Song, Y.-G., Tong, Y., & Rao, Y. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0101-6 · Cited by 663
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Authors: Churcher, I.
Affiliations: BenevolentBio, 40 Churchway, London NW1 1LW, U.K.
Corresponding author: Churcher, Ian
ORCID: Churcher, Ian
Venue: Journal of Medicinal Chemistry
Publisher: American Chemical Society (ACS)
Published: 2017-12-19
Volume: 61
Issue: 2
Pages: 444-452
ISSN: 0022-2623 (ISSN-L)
1520-4804
DOI: 10.1021/acs.jmedchem.7b01272
OpenAlex: W2769590617
Cited by: 491
References: 67
Citations by year: 2026: 45 · 2025: 61 · 2024: 49 · 2023: 56 · 2022: 53 · 2021: 54 · 2020: 84 · 2019: 64 · 2018: 22 · 2017: 1
FWCI: 4.43
Type: journal article
Language: en
Open access: closed
Locations: Journal of Medicinal Chemistry (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: targeted protein degradation, PROTACs, bifunctional small molecules, protein degradation, drug discovery
MeSH terms: Humans, Peptides, Recombinant Proteins, Drug Design, Ubiquitin-Protein Ligases, Small Molecule Libraries, Ubiquitination, Drug Discovery, Molecular Targeted Therapy, Proteolysis

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Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?

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