Cited by 377Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

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Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs

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An, Sainan, Fu, Liwu·2018·EBioMedicine

DOI 10.1016/j.ebiom.2018.09.005PMC PMC6197674

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Abstract

There are several challenges towards the development and clinical use of small molecule inhibitors, which are currently the main type of targeted therapies towards intracellular proteins. PROteolysis-TArgeting Chimeras (PROTACs) exploit the intracellular ubiquitin-proteasome system to selectively degrade target proteins. Recently, small-molecule PROTACs with high potency have been frequently reported. In this review, we summarize the emerging characteristics of small-molecule PROTACs, such as inducing a rapid, profound and sustained degradation, inducing a robust inhibition of downstream signals, displaying enhanced target selectivity, and overcoming resistance to small molecule inhibitors. In tumor xenografts, small-molecule PROTACs can significantly attenuate tumor progression. In addition, we also introduce recent developments of the PROTAC technology such as homo-PROTACs. The outstanding advantages over traditional small-molecule drugs and the promising preclinical data suggest that small-molecule PROTAC technology has the potential to greatly promote the development of targeted therapy drugs.

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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
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
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
Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein
Ohh, M., Park, C. W., Ivan, M., Hoffman, M. A., Kim, T.-Y., Huang, L. E., Pavletich, N., Chau, V., & Kaelin, W. G. (2000) · Nature Cell Biology · doi:10.1038/35017054 · Cited by 1,577
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
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
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
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
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
Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality
Arkin, M. R., Tang, Y., & Wells, J. A. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.09.001 · Cited by 1,065
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
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
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
Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide
Lopez-Girona, A., Mendy, D., Ito, T., Miller, K., Gandhi, A. K., Kang, J., Karasawa, S., Carmel, G., Jackson, P., Abbasian, M., et al. (2012) · Leukemia · doi:10.1038/leu.2012.119 · Cited by 814
The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study
Burslem, G. M., Smith, B. E., Lai, A. C., Jaime-Figueroa, S., McQuaid, D. C., Bondeson, D. P., Toure, M., Dong, H., Qian, Y., Wang, J., et al. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.009 · Cited by 686
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
Molecular Epidemiology of EGFR and KRAS Mutations in 3,026 Lung Adenocarcinomas: Higher Susceptibility of Women to Smoking-Related KRAS -Mutant Cancers
Dogan, S., Shen, R., Ang, D. C., Johnson, M. L., D'Angelo, S. P., Paik, P. K., Brzostowski, E. B., Riely, G. J., Kris, M. G., Zakowski, M. F., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-3265 · Cited by 639
Results of the CONFIRM Phase III Trial Comparing Fulvestrant 250 mg With Fulvestrant 500 mg in Postmenopausal Women With Estrogen Receptor–Positive Advanced Breast Cancer
Di Leo, A., Jerusalem, G., Petruzelka, L., Torres, R., Bondarenko, I. N., Khasanov, R., Verhoeven, D., Pedrini, J. L., Smirnova, I., Lichinitser, M. R., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.28.8415 · Cited by 636
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
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
Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation
Olson, C. M., Jiang, B., Erb, M. A., Liang, Y., Doctor, Z. M., Zhang, Z., Zhang, T., Kwiatkowski, N., Boukhali, M., Green, J. L., et al. (2018) · Nature Chemical Biology · doi:10.1038/nchembio.2538 · Cited by 552 · cited 14×
“However, small-molecule PROTACs catalytically involve in multiple rounds of target protein degradation [33,43,47].”
BackgroundInfluential
Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation
Schneekloth, J. S., Fonseca, F. N., Koldobskiy, M. A., Mandal, A., Deshaies, R. J., Sakamoto, K. M., & Crews, C. M. (2004) · Journal of the American Chemical Society · doi:10.1021/ja039025z · Cited by 507
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
EGFR Exon 20 Insertion Mutations in Lung Adenocarcinomas: Prevalence, Molecular Heterogeneity, and Clinicopathologic Characteristics
Arcila, M. E., Nafa, K., Chaft, J. E., Rekhtman, N., Lau, C., Reva, B. A., Zakowski, M. F., Kris, M. G., & Ladanyi, M. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-0620 · Cited by 473
Small-molecule kinase inhibitors: an analysis of FDA-approved drugs
Wu, P., Nielsen, T. E., & Clausen, M. H. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2015.07.008 · Cited by 457
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
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
Protein Knockdown Using Methyl Bestatin−Ligand Hybrid Molecules: Design and Synthesis of Inducers of Ubiquitination-Mediated Degradation of Cellular Retinoic Acid-Binding Proteins
Itoh, Y., Ishikawa, M., Naito, M., & Hashimoto, Y. (2010) · Journal of the American Chemical Society · doi:10.1021/ja100691p · Cited by 404
Targeting the C481S ibrutinib-resistance mutation in Bruton’s tyrosine kinase using PROTAC-mediated degradation
Buhimschi, A. D., Armstrong, H. A., Toure, M., Jaime-Figueroa, S., Chen, T. L., Lehman, A. M., Woyach, J. A., Johnson, A. J., Byrd, J. C., & Crews, C. M. (2018) · Biochemistry · doi:10.1021/acs.biochem.8b00391 · Cited by 394
Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression
Zhou, B. N., Hu, J., Xu, F., Chen, Z., Bai, L., Fernández‐Salas, E., Lin, M., Liu, L., Yang, C., Zhao, Y., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01816 · Cited by 376
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
PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies
Sun, Y., Zhao, X., Ding, N., Gao, H., Wu, Y., Yang, Y., Zhao, M., Hwang, J., Song, Y., Liu, W., et al. (2018) · Cell Research · doi:10.1038/s41422-018-0055-1 · Cited by 295
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 293
The SMARCA2/4 ATPase Domain Surpasses the Bromodomain as a Drug Target in SWI/SNF-Mutant Cancers: Insights from cDNA Rescue and PFI-3 Inhibitor Studies
Vangamudi, B., Paul, T. A., Shah, P. K., Kost-Alimova, M., Nottebaum, L., Shi, X., Zhan, Y., Leo, E., Mahadeshwar, H. S., Protopopov, A., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-3798 · Cited by 281
Chemically Induced Degradation of Sirtuin 2 (Sirt2) by a Proteolysis Targeting Chimera (PROTAC) Based on Sirtuin Rearranging Ligands (SirReals)
Schiedel, M., Herp, D., Hammelmann, S., Swyter, S., Lehotzky, A., Robaa, D., Oláh, J., Ovádi, J., Sippl, W., & Jung, M. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01872 · Cited by 277
Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1
Crew, A. P., Raina, K., Dong, H., Qian, Y., Wang, J., Vigil, D., Serebrenik, Y. V., Hamman, B. D., Morgan, A., Ferraro, C., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00635 · Cited by 257
Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation
Maniaci, C., Hughes, S. J., Testa, A., Chen, W., Lamont, D. J., Rocha, S., Alessi, D. R., Romeo, R., & Ciulli, A. (2017) · Nature Communications · doi:10.1038/s41467-017-00954-1 · Cited by 245
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
Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK)
Zhang, C., Han, X.-R., Yang, X., Jiang, B., Liu, J., Xiong, Y., & Jin, J. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.03.071 · Cited by 226
Impact of Target Warhead and Linkage Vector on Inducing Protein Degradation: Comparison of Bromodomain and Extra-Terminal (BET) Degraders Derived from Triazolodiazepine (JQ1) and Tetrahydroquinoline (I-BET726) BET Inhibitor Scaffolds
Chan, K.-H., Zengerle, M., Testa, A., & Ciulli, A. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01912 · Cited by 223
Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC)
Robb, C. M., Contreras, J. I., Kour, S., Taylor, M., Abid, M., Sonawane, Y. A., Zahid, M., Murry, D. J., Natarajan, A., & Rana, S. (2017) · Chemical Communications · doi:10.1039/c7cc03879h · Cited by 223
Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands
Gechijian, L. N., Buckley, D. L., Lawlor, M. A., Reyes, J. M., Paulk, J., Ott, C. J., Winter, G. E., Erb, M. A., Scott, T. G., Xu, M., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0010-y · Cited by 222
Small-molecule modulation of Ras signaling
Spiegel, J., Cromm, P. M., Zimmermann, G., Grossmann, T. N., & Waldmann, H. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1560 · Cited by 220
Multiplexed Proteome Dynamics Profiling Reveals Mechanisms Controlling Protein Homeostasis
Savitski, M. M., Zinn, N., Faelth-Savitski, M., Poeckel, D., Gade, S., Becher, I., Muelbaier, M., Wagner, A. J., Strohmer, K., Werner, T., et al. (2018) · Cell · doi:10.1016/j.cell.2018.02.030 · Cited by 217
Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer
Rodrı́guez-González, A., Cyrus, K., Salcius, M., Kim, K., Crews, C. M., Deshaies, R. J., & Sakamoto, K. M. (2008) · Oncogene · doi:10.1038/onc.2008.320 · Cited by 211
E3 Ubiquitin Ligases as Cancer Targets and Biomarkers
Sun, Y. (2006) · Neoplasia · doi:10.1593/neo.06376 · Cited by 210
Small‐Molecule‐Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging
Gustafson, J. L., Neklesa, T. K., Cox, C. S., Roth, A. G., Buckley, D. L., Tae, H. S., Sundberg, T. B., Stagg, D. B., Hines, J., McDonnell, D. P., et al. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201503720 · Cited by 206
Pharmacological targeting of the pseudokinase Her3
Xie, T., Lim, S. M., Westover, K. D., Dodge, M. E., Ercan, D., Ficarro, S. B., Udayakumar, D., Gurbani, D., Tae, H. S., Riddle, S. M., et al. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1658 · Cited by 205
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
BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells
Sun, B., Fiskus, W. C., Qian, Y., Rajapakshe, K., Raina, K., Coleman, K. G., Crew, A. P. A., Shen, A., Saenz, D. T., Mill, C. P., et al. (2017) · Leukemia · doi:10.1038/leu.2017.207 · Cited by 185
Translation termination factor GSPT1 is a phenotypically relevant off-target of heterobifunctional phthalimide degraders
Ishoey, M., Chorn, S., Singh, N., Jaeger, M. G., Brand, M., Paulk, J., Bauer, S., Erb, M. A., Parapatics, K., Müller, A. C., et al. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.7b00969 · Cited by 177
Development of Protein Degradation Inducers of Androgen Receptor by Conjugation of Androgen Receptor Ligands and Inhibitor of Apoptosis Protein Ligands
Shibata, N., Nagai, K., Morita, Y., Ujikawa, O., Ohoka, N., Hattori, T., Koyama, R., Sano, O., Imaeda, Y., Nara, H., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00168 · Cited by 148
Inhibitor Mediated Protein Degradation
Long, M. J. C., Gollapalli, D. R., & Hedstrom, L. (2012) · Chemistry & Biology · doi:10.1016/j.chembiol.2012.04.008 · Cited by 139
Design, Synthesis, and Biological Characterization of Metabolically Stable Selective Androgen Receptor Modulators
Marhefka, C. A., Gao, W., Chung, K., Kim, J., He, Y., Yin, D., Bohl, C. E., Dalton, J. T., & Miller, D. D. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm030336u · Cited by 136
Development of hybrid small molecules that induce degradation of estrogen receptor‐alpha and necrotic cell death in breast cancer cells
Okuhira, K., Demizu, Y., Hattori, T., Ohoka, N., Shibata, N., Nishimaki‐Mogami, T., Okuda, H., Kurihara, M., & Naito, M. (2013) · Cancer Science · doi:10.1111/cas.12272 · Cited by 132
Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in the estrogen receptor.
Connor, C. E., Norris, J. D., Broadwater, G., Willson, T. M., Gottardis, M. M., Dewhirst, M. W., & McDonnell, D. P. (2001) · PubMed · Cited by 131
Definition of Functionally Important Mechanistic Differences among Selective Estrogen Receptor Down-regulators
Wittmann, B. M., Sherk, A. B., & McDonnell, D. P. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1590 · Cited by 126
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
Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein
Okuhira, K., Ohoka, N., Sai, K., Nishimaki-Mogami, T., Itoh, Y., Ishikawa, M., Hashimoto, Y., & Naito, M. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.03.019 · Cited by 118
Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway
Ohoka, N., Nagai, K., Hattori, T., Okuhira, K., Shibata, N., Cho, N. J., & Naito, M. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.471 · Cited by 100
Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: A Useful Chemical Genetic Tool
Lee, H., Puppala, D., Choi, E., Swanson, H. I., & Kim, K. (2007) · ChemBioChem · doi:10.1002/cbic.200700438 · Cited by 96
Acquired MET expression confers resistance to EGFR inhibition in a mouse model of glioblastoma multiforme
Jun, H. J., Acquaviva, J., Chi, D., Lessard, J., Zhu, H., Woolfenden, S., Bronson, R. T., Pfannl, R., White, F., Housman, D. E., et al. (2011) · Oncogene · doi:10.1038/onc.2011.474 · Cited by 94
Androgen receptor gene mutation, rearrangement, polymorphism.
Eisermann, K., Wang, D., Jing, Y., Pascal, L. E., & Wang, Z. (2013) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2223-4683.2013.09.15 · Cited by 94
The dynamic nature of the kinome
Graves, L. M., Duncan, J. S., Whittle, M. C., & Johnson, G. L. (2013) · Biochemical Journal · doi:10.1042/bj20121456 · Cited by 93
Greasy tags for protein removal
Neklesa, T. K., & Crews, C. M. (2012) · Nature · doi:10.1038/487308a · Cited by 92
Design and synthesis of estrogen receptor degradation inducer based on a protein knockdown strategy
Demizu, Y., Okuhira, K., Motoi, H., Ohno, A., Shoda, T., Fukuhara, K., Okuda, H., Naito, M., & Kurihara, M. (2011) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2011.11.086 · Cited by 87
Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma
Zhang, X., Lee, H. C., Shirazi, F., Baladandayuthapani, V., Lin, H. Y., Kuiatse, I., Wang, H., Jones, R. J., Berkova, Z., Singh, R., et al. (2018) · Leukemia · doi:10.1038/s41375-018-0044-x · Cited by 86
Use of PROTACS as molecular probes of angiogenesis
Bargagna‐Mohan, P., Baek, S., Lee, H., Kim, K., & Mohan, R. (2005) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2005.04.008 · Cited by 70
Degradation of target protein in living cells by small-molecule proteolysis inducer
Zhang, D., Baek, S.-H., Ho, A., & Kim, K. (2003) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2003.11.042 · Cited by 64
Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer
Bradbury, R. H., Acton, D. G., Broadbent, N., Brooks, A. N., Carr, G. R., Hatter, G., Hayter, B. R., Hill, K. J., Howe, N. J., Jones, R. D. O., et al. (2013) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2013.02.056 · Cited by 56
Development of a Small Hybrid Molecule That Mediates Degradation of His-Tag Fused Proteins
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Authors: An, S., & Fu, L.
Affiliations: Sun Yat-sen University Cancer Center (CN)
Sun Yat-sen University (CN)
Corresponding author: Fu, Liwu
ORCID: Fu, Liwu
Venue: EBioMedicine
Publisher: Elsevier BV
Published: 2018-10
Volume: 36
Pages: 553-562
ISSN: 2352-3964 (ISSN-L)
DOI: 10.1016/j.ebiom.2018.09.005
PMC: PMC6197674
OpenAlex: W2890850288
Cited by: 363
References: 75
Citations by year: 2026: 36 · 2025: 40 · 2024: 57 · 2023: 37 · 2022: 57 · 2021: 55 · 2020: 46 · 2019: 35
FWCI: 3.43
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: EBioMedicine (publishedVersion, cc-by-nc-nd)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders: Natural Science Foundation of Guangdong Province (2016A030312014)
National Key Scientific Instrument and Equipment Development Projects of China (2018ZX09711002-003-011)
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
Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Keywords: PROTACs, targeted protein degradation, ubiquitin-proteasome system, target selectivity, drug resistance, tumor xenografts, intracellular protein degradation, targeted therapy
MeSH terms: Animals, Antineoplastic Agents, Humans, Signal Transduction, Biomarkers, Proteasome Endopeptidase Complex, Small Molecule Libraries, Ubiquitination, Drug Discovery, Molecular Targeted Therapy, Proteolysis, Proteasome Inhibitors

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Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs

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