MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53
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Abstract
Although the number of proteins effectively targeted for posttranslational degradation by PROTAC has grown steadily, the number of E3 ligases successfully exploited to accomplish this has been limited to the few for which small-molecule ligands have been discovered. Although the E3 ligase MDM2 is bound by the nutlin class of small-molecule ligands, there are few nutlin-based PROTAC. Because a nutlin-based PROTAC should both knockdown its target protein and upregulate the tumor suppressor p53, we examined the ability of such a PROTAC to decrease cancer cell viability. A nutlin-based, BRD4-degrading PROTAC, A1874, was able to degrade its target protein by 98% with nanomolar potency. Given the complementary ability of A1874 to stabilize p53, we discovered that the nutlin-based PROTAC was more effective in inhibiting proliferation of many cancer cell lines with wild-type p53 than was a corresponding VHL-utilizing PROTAC with similar potency and efficacy to degrade BRD4. This is the first report of a PROTAC in which the E3 ligase ligand and targeting warhead combine to exert a synergistic antiproliferative effect. Our study highlights the untapped potential that may be unlocked by expanding the repertoire of E3 ligases that can be recruited by PROTAC. Significance: These findings present the first BRD4-targeting MDM2-based PROTAC that possesses potent, distinct, and synergistic biological activities associated with both ends of this heterobifunctional molecule.
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A1874 degraded BRD4 almost completely in HCT116 cells at 100 nM within 24 h.
“This PROTAC, A1874, degraded BRD4 almost completely in HCT116 cells at 100 nM within 24 h.”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [68]
A MDM2-based PROTAC could synergistically combine a catalytic mechanism of action, via degradation of a neo-substrate, and an occupancy-based effect, via competition with and stabilization of the endogenous substrate p53.
“It was recently shown that a MDM2-based PROTAC could synergistically combine a catalytic mechanism of action, via degradation of a neo-substrate, and an occupancy-based effect, via competition with, and stabilization of, the endogenous substrate p53 (ref. 60 ).”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [60]
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Cites
Selective inhibition of BET bromodomains
Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W. B., Fedorov, O., Morse, E. M., Keates, T., Hickman, T. T., Felletar, I., et al. (2010) · Nature · doi:10.1038/nature09504 · Cited by 4,262 · see citing works
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 · see citing works
Self-citationIdentification 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
RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia
Zuber, J., Shi, J., Wang, E., Rappaport, A. R., Herrmann, H., Sison, E. A., Magoon, D., Qi, J., Blatt, K., Wunderlich, M., et al. (2011) · Nature · doi:10.1038/nature10334 · Cited by 1,870 · see citing works
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 · see citing works
Ubiquitin ligases: structure, function, and regulation
Zheng, N., & Shabek, N. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060815-014922 · Cited by 1,499 · 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
Self-citationStructural 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
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 · see citing works
Self-citationAnalysis of drug combinations: current methodological landscape
Foucquier, J., & Guedj, M. (2015) · Pharmacology Research & Perspectives · doi:10.1002/prp2.149 · Cited by 1,115 · 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
Self-citationBanaszynski, L. A., Chen, L.-C., Maynard-Smith, L. A., Ooi, A. G. L., & Wandless, T. J. (2006) · Cell · doi:10.1016/j.cell.2006.07.025 · Cited by 902 · see citing works
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 · see citing works
Self-citationThe 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 · see citing works
Self-citationSchneekloth, 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 · see citing works
Self-citationModular 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 · see citing works
Self-citationTargeted 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 · see citing works
Self-citationDiscovery of RG7388, a Potent and Selective p53–MDM2 Inhibitor in Clinical Development
Ding, Q., Zhang, Z., Liu, J.-J., Jiang, N., Zhang, J., Ross, T. M., Chu, X.-J., Bartkovitz, D., Podlaski, F., Janson, C., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400487c · Cited by 595 · see citing works
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 3× · see citing works
“both contexts – the research lab and the clinic -- PROTACs have received recent attention, leading to the generation of PROTACs that degrade cyclin-dependent kinases (12), lipid kinases (13), peptidases (4), protein isomerases (5), scaffolding proteins (13), transcription factors (3,11,14), protein kinases (1,10,15-18…”
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 502 · see citing works
Self-citationProtac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?
Churcher, I. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01272 · Cited by 491 · 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
Self-citationA 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
Itoh, Y., Ishikawa, M., Naito, M., & Hashimoto, Y. (2010) · Journal of the American Chemical Society · doi:10.1021/ja100691p · Cited by 404 · see citing works
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 · see citing works
Self-citationSalami, J., Alabi, S., Willard, R. R., Vitale, N. J., Wang, J., Dong, H., Jin, M., McDonnell, D. P., Crew, A. P., Neklesa, T. K., et al. (2018) · Communications Biology · doi:10.1038/s42003-018-0105-8 · Cited by 349 · see citing works
Self-citationSmall‐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 · see citing works
Self-citationSmall-Molecule Modulation of Protein Homeostasis
Burslem, G. M., & Crews, C. M. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00077 · Cited by 294 · see citing works
Self-citationFunctional genomics identifies therapeutic targets for MYC-driven cancer
Toyoshima, M., Howie, H. L., Imakura, M., Walsh, R. M., Annis, J. E., Chang, A. N., Frazier, J. P., Chau, B. N., Loboda, A. P., Linsley, P. S., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1121119109 · Cited by 245 · see citing works
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 · see citing works
Impact of linker length on the activity of PROTACs
Cyrus, K., Wehenkel, M., Choi, E.-Y., Han, H.-J., Lee, H., Swanson, H., & Kim, K.-B. (2010) · Molecular BioSystems · doi:10.1039/c0mb00074d · Cited by 232 · see citing works
Chan, K.-H., Zengerle, M., Testa, A., & Ciulli, A. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01912 · Cited by 222 · see citing works
CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer
McCleland, M. L., Mesh, K., Lorenzana, E. G., Chopra, V. S., Segal, E., Watanabe, C. K., Haley, B., Mayba, O., Yaylaoglu, M., Gnad, F., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci83265 · Cited by 220 · see citing works
Bhadury, J., Nilsson, L. M., Muralidharan, S. V., Green, L. C., Li, Z., Gesner, E. M., Hansen, H. C., Keller, U. B., McLure, K. G., & Nilsson, J. A. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1406722111 · Cited by 215 · see citing works
Small-molecule displacement of a cryptic degron causes conditional protein degradation
Bonger, K. M., Chen, L., Liu, C. W., & Wandless, T. J. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.598 · Cited by 207 · see citing works
Hines, J. F., Gough, J. D., Corson, T. W., & Crews, C. M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1217206110 · Cited by 177 · see citing works
Self-citationAssessing 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
Self-citationBET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer
Karakashev, S. V., Zhu, H., Yokoyama, Y., Zhao, B., Fatkhutdinov, N., Kossenkov, A. V., Wilson, A. J., Simpkins, F. A., Speicher, D. W., Khabele, D., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.11.095 · Cited by 175 · see citing works
Small Molecules Destabilize cIAP1 by Activating Auto-ubiquitylation
Sekine, K., Takubo, K., Kikuchi, R., Nishimoto, M., Kitagawa, M., Abe, F., Nishikawa, K., Tsuruo, T., & Naito, M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m709525200 · Cited by 173 · see citing works
Chaidos, A., Caputo, V. S., & Karadimitris, A. (2015) · Therapeutic Advances in Hematology · doi:10.1177/2040620715576662 · Cited by 166 · see citing works
Targeting the Undruggable Proteome: The Small Molecules of My Dreams
Crews, C. M. (2010) · Chemistry & Biology · doi:10.1016/j.chembiol.2010.05.011 · Cited by 147 · see citing works
Self-citationOkuhira, 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 130 · see citing works
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 111 · see citing works
Self-citationOhoka, N., Morita, Y., Nagai, K., Shimokawa, K., Ujikawa, O., Fujimori, I., Ito, M., Hayase, Y., Okuhira, K., Shibata, N., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001091 · Cited by 105 · see citing works
BRD4 Inhibitor Inhibits Colorectal Cancer Growth and Metastasis
Hu, Y., Zhou, J., Ye, F., Xiong, H., Peng, L., Zheng, Z., Xu, F., Cui, M., Wei, C., Wang, X., et al. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms16011928 · Cited by 94 · see citing works
Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors
Kalan, S., Amat, R., Schachter, M. M., Kwiatkowski, N. P., Abraham, B. J., Liang, Y., Zhang, T., Olson, C. M., Larochelle, S., Young, R. A., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.056 · Cited by 74 · see citing works
BET inhibitors in the treatment of hematologic malignancies: current insights and future prospects
Munshi, H., Abedin, S., & Boddy, C. (2016) · OncoTargets and Therapy · doi:10.2147/ott.s100515 · Cited by 71 · see citing works
Puppala, D., Lee, H., Kim, K. B., & Swanson, H. I. (2008) · Molecular Pharmacology · doi:10.1124/mol.107.040840 · Cited by 70 · see citing works
He, S., Dong, G., Wu, S., Fang, K., Miao, Z., Wang, W., & Sheng, C. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00664 · Cited by 68 · see citing works
Wu, C., Esfandiari, A., Ho, Y.-H., Wang, N., Mahdi, A. K., Aptullahoğlu, E., Lovat, P. E., & Lunec, J. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.433 · Cited by 62 · see citing works
Two‐Headed PROTAC: An Effective New Tool for Targeted Protein Degradation
Cyrus, K., Wehenkel, M., Choi, E., Swanson, H. I., & Kim, K. (2010) · ChemBioChem · doi:10.1002/cbic.201000222 · Cited by 59 · see citing works
Targeting c-Myc: JQ1 as a promising option for c-Myc-amplified esophageal squamous cell carcinoma
Wang, J., Liu, Z., Wang, Z., Wang, S., Chen, Z., Li, Z., Zhang, M., Zou, J., Dong, B., Gao, J., et al. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.01.051 · Cited by 53 · see citing works
Laroche, A., Chaire, V., Algeo, M.-P., Karanian, M., Fourneaux, B., & Italiano, A. (2017) · Oncotarget · doi:10.18632/oncotarget.16345 · Cited by 38 · see citing works
Nutlin‐3a as a novel anticancer agent for adrenocortical carcinoma with CTNNB1 mutation
Wen, H., Liu, S., Zheng, J., Fang, Z., Ding, Q., & Feng, C. (2018) · Cancer Medicine · doi:10.1002/cam4.1431 · Cited by 22 · see citing works
Wang, X., Zhang, S., Bao, J., & Liu, F. (2017) · Tumor Biology · doi:10.1177/1010428317701638 · Cited by 19 · see citing works
Flagged first, then by citations
1 of the 56 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Exploring treatment options in cancer: tumor treatment strategies
Liu, B., Zhou, H., Tan, L., Siu, K. T. H., & Guan, X.-Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01856-7 · Cited by 1,201 · 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
Self-citationTargeted 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
Self-citationPROteolysis TArgeting Chimeras (PROTACs) — Past, present and future
Pettersson, M., & Crews, C. M. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2019.01.002 · Cited by 818 · see citing works
Self-citationDrugging p53 in cancer: one protein, many targets
Hassin, O., & Oren, M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00571-8 · Cited by 736 · see citing works
Advancing targeted protein degradation for cancer therapy
Dale, B., Cheng, M., Park, K., Kanıskan, H. Ü., Xiong, Y., & Jin, J. J. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00365-x · Cited by 671 · see citing works
Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy
Li, X., & Song, Y. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00885-3 · Cited by 550 · see citing works
PROTACs: An Emerging Therapeutic Modality in Precision Medicine
Nalawansha, D. A., & Crews, C. M. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.07.020 · Cited by 514 · see citing works
Self-citationDevelopment of targeted protein degradation therapeutics
Chamberlain, P. P., & Hamann, L. G. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0362-y · Cited by 489 · see citing works
E3 ubiquitin ligases: styles, structures and functions
Yang, Q., Zhao, J., Chen, D., & Wang, Y. (2021) · Molecular Biomedicine · doi:10.1186/s43556-021-00043-2 · Cited by 435 · see citing works
Targeted protein degradation: from mechanisms to clinic
Tsai, J. M., Nowak, R. P., Ebert, B. L., & Fischer, E. S. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00729-9 · Cited by 438 · see citing works
Current strategies for the design of PROTAC linkers: a critical review
Troup, R. I., Fallan, C., & Baud, M. G. J. (2020) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2020.00018 · Cited by 424 · see citing works
Edmondson, S. D., Yang, B., & Fallan, C. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.04.030 · Cited by 422 · see citing works
E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones
Ishida, T., & Ciulli, A. (2020) · SLAS DISCOVERY · doi:10.1177/2472555220965528 · Cited by 395 · see citing works
Proteolysis-targeting chimeras (PROTACs) in cancer therapy
Li, X., Pu, W., Zheng, Q., Ai, M., Chen, S., & Peng, Y. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01434-3 · Cited by 374 · 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
An overview of PROTACs: a promising drug discovery paradigm
Zi, L., Hu, M., Yu, Y., Du, C., Zhou, H., Liu, C., Chen, Y., Fan, L., Ma, H., Gong, Y., et al. (2022) · Molecular Biomedicine · doi:10.1186/s43556-022-00112-0 · Cited by 366 · see citing works
Degradation of proteins by PROTACs and other strategies
Wang, Y., Jiang, X., Feng, F., Liu, W., & Sun, H. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2019.08.001 · Cited by 335 · see citing works
Targeted protein degradation: advances in drug discovery and clinical practice
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PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy
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Self-citationZeng, S., Huang, W., Zheng, X., Cheng, L., Zhang, Z., Wang, J., & Shen, Z. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112981 · Cited by 262 · see citing works
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Bond, M. J., & Crews, C. M. (2021) · RSC Chemical Biology · doi:10.1039/d1cb00011j · Cited by 227 · see citing works
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Bricelj, A., Steinebach, C., Kuchta, R. D., Gütschow, M., & Sosič, I. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.707317 · Cited by 226 · see citing works
Antibody Conjugation of a Chimeric BET Degrader Enables <i>in vivo</i> Activity
Pillow, T. H., Adhikari, P., Blake, R. A., Chen, J., Del Rosario, G., Deshmukh, G., Figueroa, I., Gascoigne, K. E., Kamath, A. V., Kaufman, S., et al. (2020) · ChemMedChem · doi:10.1002/cmdc.201900497 · Cited by 216 · see citing works
Translating p53-based therapies for cancer into the clinic
Peuget, S., Zhou, X., & Selivanova, G. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-023-00658-3 · Cited by 198 · see citing works
Expanding PROTACtable genome universe of E3 ligases
Liu, Y., Yang, J., Wang, T., Luo, M., Chen, Y., Chen, C., Ronai, Z. A., Zhou, Y., Ruppin, E., & Han, L. (2023) · Nature Communications · doi:10.1038/s41467-023-42233-2 · Cited by 193 · 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 182 · see citing works
PROTACs: A novel strategy for cancer therapy
Liu, J., Ma, J., Liu, Y., Xia, J., Li, Y., Wang, Z. P., & Wei, W. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.02.006 · 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
E3 ligase ligand chemistries: from building blocks to protein degraders
Sosič, I., Bricelj, A., & Steinebach, C. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00148a · Cited by 173 · see citing works
PROTACs– a game-changing technology
Konstantinidou, M., Li, J., Zhang, B., Wang, Z., Shaabani, S., ter Brake, F., Essa, K., & Dömling, A. S. S. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2019.1659242 · Cited by 167 · 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
Developing degraders: principles and perspectives on design and chemical space
Maple, H. J., Clayden, N., Baron, A., Stacey, C., & Felix, R. L. (2019) · MedChemComm · doi:10.1039/c9md00272c · Cited by 159 · see citing works
The role of reversible and irreversible covalent chemistry in targeted protein degradation
Kiely‐Collins, H., Winter, G. E., & Bernardes, G. J. L. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.03.005 · Cited by 156 · see citing works
Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation
Wei, J., Meng, F., Park, K.-S., Yim, H., Velez, J., Kumar, P., Wang, L., Xie, L., Chen, H., Shen, Y., et al. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c04841 · Cited by 154 · see citing works
Mutant-selective degradation by BRAF-targeting PROTACs
Alabi, S., Jaime-Figueroa, S., Yao, Z., Gao, Y., Hines, J., Samarasinghe, K. T. G., Vogt, L., Rosen, N., & Crews, C. M. (2021) · Nature Communications · doi:10.1038/s41467-021-21159-7 · Cited by 152 · see citing works
Self-citationDragovich, P. S., Pillow, T. H., Blake, R. A., Sadowsky, J. D., Adaligil, E., Adhikari, P., Bhakta, S., Blaquiere, N., Chen, J., dela Cruz-Chuh, J., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01845 · Cited by 152 · see citing works
Expanding the arsenal of E3 ubiquitin ligases for proximity-induced protein degradation
Kannt, A., & Đikić, I. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.04.007 · Cited by 149 · see citing works
An E3 ligase guide to the galaxy of small-molecule-induced protein degradation
Jevtić, P., Haakonsen, D. L., & Rapé, M. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.04.002 · Cited by 144 · see citing works
Characteristic roadmap of linker governs the rational design of PROTACs
Dong, Y., Ma, T., Xu, T., Feng, Z., Li, Y., Song, L., Yao, X., Ashby, C. R., & Hao, G.-F. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.04.007 · Cited by 146 · see citing works
Steinebach, C., Ng, Y. L. D., Sosič, I., Lee, C.-S., Chen, S., Lindner, S., Vu, L. P., Bricelj, A., Haschemi, R., Monschke, M., et al. (2020) · Chemical Science · doi:10.1039/d0sc00167h · Cited by 148 · see citing works
Ligandability of E3 Ligases for Targeted Protein Degradation Applications
Belcher, B. P., Ward, C. C., & Nomura, D. K. (2023) · Biochemistry · doi:10.1021/acs.biochem.1c00464 · Cited by 132 · see citing works
Discovery of E3 Ligase Ligands for Target Protein Degradation
Lee, J., Lee, Y., Jung, Y. M., Park, J. H., Yoo, H. S., & Park, J. (2022) · Molecules · doi:10.3390/molecules27196515 · Cited by 125 · see citing works
Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies
He, Y., Khan, S., Huo, Z., Lv, D., Zhang, X., Liu, X., Yuan, Y., Hromas, R., Xu, M., Zheng, G., et al. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00924-z · Cited by 126 · see citing works
Bashraheel, S. S., Dömling, A. S. S., & Goda, S. K. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110009 · Cited by 122 · see citing works
Strategies for designing proteolysis targeting chimaeras (PROTACs)
He, S., Dong, G., Cheng, J., Wu, Y., & Sheng, C. (2022) · Medicinal Research Reviews · doi:10.1002/med.21877 · Cited by 118 · see citing works
Development of Small Molecule Chimeras That Recruit AhR E3 Ligase to Target Proteins
Ohoka, N., Tsuji, G., Shoda, T., Fujisato, T., Kurihara, M., Demizu, Y., & Naito, M. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00704 · Cited by 117 · see citing works
A bibliometric analysis of PROTAC from 2001 to 2021
Li, D., Yu, D., Li, Y., & Yang, R. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114838 · Cited by 122 · see citing works
A Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL
Tong, B., Spradlin, J. N., Novaes, L. F. T., Zhang, E., Hu, X., Moeller, M., Brittain, S. M., McGregor, L. M., McKenna, J. M., Tallarico, J. A., et al. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00348 · Cited by 118 · see citing works
Yan, S., Yan, J., Liu, D., Li, X., Kang, Q., You, W., Zhang, J., Wang, L., Tian, Z., Lu, W., et al. (2021) · Theranostics · doi:10.7150/thno.59020 · Cited by 107 · see citing works
Super-enhancers and the super-enhancer reader BRD4: tumorigenic factors and therapeutic targets
Qian, H., Zhu, M., Tan, X., Zhang, Y., Liu, X., & Yang, L. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01775-6 · Cited by 106 · see citing works
Regulation of programmed cell death by Brd4
Hu, J., Pan, D., Guo, L., Chen, K., & Hu, X. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05505-1 · Cited by 96 · see citing works
Advances in targeted degradation of endogenous proteins
Röth, S., Fulcher, L. J., & Sapkota, G. P. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03112-6 · Cited by 92 · see citing works
Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer
He, S., Ma, J., Fang, Y., Liu, Y., Wu, S., Dong, G., Wang, W., & Sheng, C. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.11.022 · Cited by 91 · see citing works
Targeting Biomolecular Condensation and Protein Aggregation against Cancer
Silva, J. L., Foguel, D., Ferreira, V. F., Vieira, T. C. R. G., Marques, M. A., Ferretti, G. D. S., Outeiro, T. F., Cordeiro, Y., & de Oliveira, G. A. P. (2023) · Chemical Reviews · doi:10.1021/acs.chemrev.3c00131 · Cited by 85 · see citing works
Tomoshige, S., & Ishikawa, M. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202004746 · Cited by 84 · see citing works
PROTAC: A promising technology for cancer treatment
Zhou, X., Dong, R., Zhang, J., Zheng, X. X., & Sun, L. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112539 · Cited by 84 · see citing works
Piperlongumine conjugates induce targeted protein degradation
Pei, J., Xiao, Y., Liu, X., Hu, W., Sobh, A., Yuan, Y., Zhou, S., Hua, N., Mackintosh, S. G., Zhang, X., et al. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.01.004 · Cited by 84 · see citing works
Peng, X., Hu, Z., Zeng, L., Zhang, M., Xu, C., Lu, B., Tao, C., Chen, W., Hou, W., Cheng, K., et al. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.09.003 · Cited by 85 · see citing works
Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors
LaPlante, G., & Zhang, W. (2021) · Cancers · doi:10.3390/cancers13123079 · Cited by 82 · see citing works
Lim, S., Khoo, R., Juang, Y.-C., Gopal, P., Zhang, H., Yeo, C., Peh, K. M., Teo, J., Ng, S., Henry, B., et al. (2021) · ACS Central Science · doi:10.1021/acscentsci.0c01337 · Cited by 80 · see citing works
Development of selective small molecule MDM2 degraders based on nutlin
Wang, B., Wu, S., Liu, J., Yang, K., Xie, H., & Tang, W. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.05.046 · Cited by 77 · see citing works
Recent Advances in PROTACs for Drug Targeted Protein Research
Yao, T., Xiao, H., Wang, H., & Xu, X. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810328 · Cited by 78 · see citing works
Advancing targeted protein degradation for metabolic diseases therapy
Zhou, Q., Xiao, H., Yang, F., Wang, Y., Li, P., & Zheng, Z. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106627 · Cited by 76 · see citing works
Advancing Strategies for Proteolysis-Targeting Chimera Design
Li, M., Zhi, Y., Liu, B., & Yao, Q. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01555 · Cited by 76 · see citing works
Designing Chimeric Molecules for Drug Discovery by Leveraging Chemical Biology
Borsari, C., Trader, D. J., Tait, A., & Costi, M. P. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01456 · Cited by 75 · see citing works
Watt, G. F., Scott‐Stevens, P., & Gaohua, L. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2019.02.005 · Cited by 72 · see citing works
Han, B. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.014715 · Cited by 69 · see citing works
The rise of covalent proteolysis targeting chimeras
Gabizon, R., & London, N. (2021) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2020.12.003 · Cited by 70 · see citing works
Expanding the landscape of E3 ligases for targeted protein degradation
Kramer, L. T. S., & Zhang, X. (2022) · Current Research in Chemical Biology · doi:10.1016/j.crchbi.2022.100020 · Cited by 69 · see citing works
PROTACs: A novel strategy for cancer drug discovery and development
Han, X., & Sun, Y. (2023) · MedComm · doi:10.1002/mco2.290 · Cited by 67 · see citing works
PROTAC degraders with ligands recruiting MDM2 E3 ubiquitin ligase: an updated perspective
Han, X., Wei, W., & Sun, Y. (2022) · Acta Materia Medica · doi:10.15212/amm-2022-0010 · Cited by 67 · see citing works
The therapeutic effect of the BRD4-degrading PROTAC A1874 in human colon cancer cells
Qin, A., Jin, H., Song, Y., Gao, Y. L., Chen, Y., Zhou, L.-N., Wang, S., & Lu, X. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-03015-6 · Cited by 66 · see citing works
Applications of covalent chemistry in targeted protein degradation
Lu, D., Yu, X., Lin, H., Cheng, R., Monroy, E. Y., Qi, X., Wang, M. C., & Wang, J. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00362g · Cited by 66 · see citing works
Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries
Wang, B., Liu, J., Tandon, I., Wu, S., Teng, P., Liao, J., & Tang, W. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113425 · Cited by 67 · see citing works
It’s Getting Complicated—A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy
Kung, C.-P., & Weber, J. D. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.818744 · Cited by 68 · see citing works
Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery
Pei, H., Peng, Y., Zhao, Q., & Chen, Y. (2019) · RSC Advances · doi:10.1039/c9ra03423d · Cited by 65 · see citing works
Proteolysis-Targeting Chimeras (PROTACs) in Cancer Therapy: Present and Future
Li, R., Liu, M., Yang, Z., Li, J., Gao, Y., & Tan, R. (2022) · Molecules · doi:10.3390/molecules27248828 · Cited by 64 · see citing works
Mayuri, K., Sreeraman, S., Somala, C. S., Kushwah, R. B. S., Saravanan, K. M., Sundaram, V., & Anand, T. (2023) · Future Medicinal Chemistry · doi:10.4155/fmc-2023-0072 · Cited by 63 · see citing works
A patent review of BRD4 inhibitors (2013-2019)
Lu, T., Lu, W., & Luo, C. (2019) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2020.1702645 · Cited by 64 · see citing works
Journey of PROTAC: From Bench to Clinical Trial and Beyond
Berkley, K., Zalejski, J., Sharma, N., & Sharma, A. K. (2025) · Biochemistry · doi:10.1021/acs.biochem.4c00577 · Cited by 62 · see citing works
Current advances of small molecule E3 ligands for proteolysis-targeting chimeras design
Mi, D., Li, Y., Gu, H., Li, Y., & Chen, Y. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115444 · Cited by 57 · see citing works
A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation
Fletcher, A., Clift, D., de Vries, E., Cuesta, S. M., Malcolm, T., Meghini, F., Chaerkady, R., Wang, J., Chiang, A. J., Weng, S. H. S., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42546-2 · Cited by 56 · see citing works
Small molecule PROTACs in targeted therapy: An emerging strategy to induce protein degradation
Xi, M., Chen, Y., Yang, H., Xu, H., Du, K., Wu, C., Xu, Y., Deng, L., Luo, X., Yu, L., et al. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.04.036 · Cited by 56 · see citing works
Recent Advances in PROTAC-Based Antiviral Strategies
Ahmad, H., Zia, B., Husain, H., & Husain, A. (2023) · Vaccines · doi:10.3390/vaccines11020270 · Cited by 54 · see citing works
Duan, Y., Liu, W., Tian, L., Mao, Y., & Song, C. (2019) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026619666190618130008 · Cited by 54 · see citing works
A critical evaluation of the approaches to targeted protein degradation for drug discovery
Chopra, R., Sadok, A., & Collins, I. (2019) · Drug Discovery Today: Technologies · doi:10.1016/j.ddtec.2019.02.002 · Cited by 53 · see citing works
Moon, Y., Jeon, S. I., Shim, M. K., & Kim, K. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15020411 · Cited by 55 · see citing works
Vicente, A. T. S., & Salvador, J. A. R. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911068 · Cited by 53 · see citing works
Maity, P., Chatterjee, J., Patil, K. T., Arora, S., Katiyar, M. K., Kumar, M., Samarbakhsh, A., Joshi, G., Bhutani, P., Chugh, M., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01242 · Cited by 51 · see citing works
A CRISPR activation screen identifies FBXO22 supporting targeted protein degradation
Basu, A. A., Zhang, C., Riha, I. A., Magassa, A., Campos, M. A. L., Caldwell, A. G., Ko, F., & Zhang, X. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01655-9 · Cited by 50 · see citing works
Jiang, F., Wei, Q., Li, H., Li, H., Cui, Y., Ma, Y., Chen, H., Cao, P., Lu, T., & Chen, Y. (2020) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2019.115181 · Cited by 48 · see citing works
The impact of E3 ligase choice on PROTAC effectiveness in protein kinase degradation
Sobierajski, T., Małolepsza, J., Pichlak, M., Gendaszewska‐Darmach, E., & Błażewska, K. M. (2024) · Drug Discovery Today · doi:10.1016/j.drudis.2024.104032 · Cited by 48 · see citing works
Selectivity through Targeted Protein Degradation (TPD)
Gopalsamy, A. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00397 · Cited by 46 · see citing works
A balancing act: using small molecules for therapeutic intervention of the p53 pathway in cancer
Miller, J. J., Gaiddon, C., & Storr, T. (2020) · Chemical Society Reviews · doi:10.1039/d0cs00163e · Cited by 46 · see citing works
- Authors
- Hines, J., Lartigue, S., Dong, H., Qian, Y., & Crews, C. M.
- Affiliations
- Yale University (US)
- Arvinas (United States) (US)
- Corresponding author
- Crews, Craig M.
- Venue
- Cancer Research
- Published
- 2019-01-01
- Volume
- 79
- Issue
- 1
- Pages
- 251-262
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC6318015
- OpenAlex
- W2898621430
- Cited by
- 348
- References
- 56
- Citations by year
- 2026: 30 · 2025: 49 · 2024: 52 · 2023: 41 · 2022: 60 · 2021: 45 · 2020: 45 · 2019: 25 · 2014: 1
- FWCI
- 10.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NCI (R50 CA211252)
- NIH (R35 CA197589)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- PROTACs, MDM2, BRD4 degradation, p53 stabilization, nutlin, E3 ubiquitin ligase, VHL, antiproliferative activity, drug synergy, heterobifunctional molecules, tumor cell proliferation
- MeSH terms
- Bromodomain Containing Proteins, Drug Synergism, Fibrinolytic Agents, Humans, Neoplasms, Nuclear Proteins, Peptides, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Cell Cycle Proteins, Cell Proliferation, Proto-Oncogene Proteins c-mdm2, Protein Stability, Proteolysis
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