First targeted protein degrader hits the clinic
Open accessThe claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A first heterobifunctional PROTAC that recruits the androgen receptor to an E3 ligase recently entered the clinic.
“Finally, a first heterobifunctional PROTAC that recruits the androgen receptor to an E3 ligase recently entered the clinic 21 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [21]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cited by
Sorted by citations
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
Trends in kinase drug discovery: targets, indications and inhibitor design
Attwood, M. M., Fabbro, D., Sokolov, A. V., Knapp, S., & Schiöth, H. B. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00252-y · Cited by 807 · see citing works
Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones
Liang, D., Feng, Y., Zandkarimi, F., Wang, H., Zhang, Z., Kim, J., Cai, Y., Gu, W. J., Stockwell, B. R., & Jiang, X. (2023) · Cell · doi:10.1016/j.cell.2023.05.003 · Cited by 739 · see citing works
“ARV-110 is a clinical stage PROTAC protein degrader selectively targetingAR.(41)Remarkably, bothENZandARV-110 inhibited endogenous MBOAT2 expression in a dose-dependent manner (Figures 5A, 5C, and S5H) and strongly sensitizedmultiple AR PCa cell lines to RSL3-induced ferroptosis, including CRPC line LnAR (Figures 5A–5…”
BackgroundLYTACs that engage the asialoglycoprotein receptor for targeted protein degradation
Ahn, G., Banik, S. M., Miller, C. L., Riley, N. M., Cochran, J. R., & Bertozzi, C. R. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00770-1 · Cited by 654 · 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
Development 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
Challenges and Opportunities in Cancer Drug Resistance
Ward, R. A., Fawell, S. E., Floc’h, N., Flemington, V., McKerrecher, D., & Smith, P. D. (2020) · Chemical Reviews · doi:10.1021/acs.chemrev.0c00383 · Cited by 454 · 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
Advances in Targeting ‘Undruggable’ transcription Factors With Small Molecules
Henley, M. J., & Koehler, A. N. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00199-0 · Cited by 409 · 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
“The development of the PROTAC technology for the treatment of cancer has ultimately culminated in the first two degraders (both from Arvinas, undisclosed structures) recently reaching phase 1 clinical trials, where their safety and tolerability are being assessed through dose-escalation [57].”
MethodTargeted protein degradation: advances in drug discovery and clinical practice
Zhong, G., Chang, X., Xie, W., & Zhou, X. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02004-x · Cited by 326 · see citing works
Impact of Cross-Coupling Reactions in Drug Discovery and Development
Buskes, M. J., & Blanco, M.-J. (2020) · Molecules · doi:10.3390/molecules25153493 · Cited by 296 · see citing works
“PROTACs have become a new chemical modality [51] with some companies like Arvinas being pioneers [69] and any other phar aceutical co panies focusing on this approach.”
BackgroundPance, K., Gramespacher, J. A., Byrnes, J. R., Salangsang, F., Serrano, J.-A. C., Cotton, A. D., Steri, V., & Wells, J. A. (2023) · Nature Biotechnology · doi:10.1038/s41587-022-01456-2 · Cited by 265 · see citing works
Surka, C., Jin, L., Mbong, N., Lu, C.-C., Jang, I. S., Rychak, E., Mendy, D., Clayton, T., Tindall, E., Hsu, C., et al. (2021) · Blood · doi:10.1182/blood.2020008676 · Cited by 229 · see citing works
Ubiquitin ligases: guardians of mammalian development
Walma, D. A. C., Chen, Z., Bullock, A. N., & Yamada, K. M. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00448-5 · Cited by 212 · see citing works
Efficient targeted degradation via reversible and irreversible covalent PROTACs
Gabizon, R., Shraga, A., Gehrtz, P., Livnah, E., Gurwicz, N., Avram, L., Unger, T., Albeck, S., Shulman, Z., & London, N. (2020) · doi:10.26434/chemrxiv.11494398.v1 · Cited by 213 · see citing works
Cecchini, C., Pannilunghi, S., Tardy, S., & Scapozza, L. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.672267 · Cited by 198 · see citing works
“Moreover, phase I clinical trials of oral administrated PROTACs (ARV-110 and ARV-471) targeting androgen and estrogen receptors are ongoing, respectively tested for prostate and breast cancer (Neklesa et al., 2017; Flanagan et al., 2019; Mullard, 2019).”
BackgroundAhn, G., Riley, N. M., Kamber, R. A., Wisnovsky, S., von Hase, S. M., Bassik, M. C., Banik, S. M., & Bertozzi, C. R. (2023) · Science · doi:10.1126/science.adf6249 · Cited by 197 · see citing works
“Intra-cellular degradation approaches using proteolysis-targetingchimeras(PROTACs) ( 1 , 2 ) or molecular glues ( 3 , 4 ), both of which recruit E3 ligases to promote ubiquitination of target proteins, have already demonstrated clinicalimpact ( 5 , 6 ).”
Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader
Potjewyd, F., Turner, A. W., Beri, J., Rectenwald, J. M., Norris-Drouin, J. L., Cholensky, S. H., Margolis, D. M., Pearce, K. H., Herring, L. E., & James, L. I. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.11.006 · Cited by 179 · 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
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
Han, X., Zhao, L., Xiang, W., Qin, C., Miao, B., McEachern, D., Wang, Y., Metwally, H., Wang, L., Matvekas, A., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00882 · Cited by 170 · 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
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
Aptamer-Based Targeted Protein Degradation
Liu, Y., Qian, X., Ran, C., Li, L., Fu, T., Su, D., Xie, S., & Tan, W. (2023) · ACS Nano · doi:10.1021/acsnano.2c10379 · Cited by 106 · see citing works
Enzymatic Logic of Ubiquitin Chain Assembly
Deol, K. K., Lorenz, S., & Strieter, E. R. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00835 · Cited by 107 · see citing works
“…chain formation will facilitate the development of bifunctional small molecules, known as PROTACs (Sakamoto et al., 2002), that re-program a particular ligase to mark a pathogenic target protein for degradation – a powerful concept that has recently entered clinical trials (Mullard, 2019).”
BackgroundTarget protein localization and its impact on PROTAC-mediated degradation
Simpson, L. M., Glennie, L., Brewer, A., Zhao, J., Crooks, J., Shpiro, N., & Sapkota, G. P. (2022) · Cell chemical biology · doi:10.1016/j.chembiol.2022.08.004 · Cited by 100 · see citing works
Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins
Lin, J., Jin, J., Shen, Y., Zhang, L., Gong, G., Bian, H., Chen, H., Nagle, D. G., Wu, Y., Zhang, W., et al. (2021) · Theranostics · doi:10.7150/thno.62686 · Cited by 98 · see citing works
“with large shallow surfaces as well as extracellular proteins [10,33-35].”
BackgroundXie, S., Zhu, J., Li, J., Zhan, F., Yao, H., Xu, J., & Xu, S. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00736 · Cited by 109 · 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
Ahn, G., Banik, S. M., & Bertozzi, C. R. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.02.024 · Cited by 96 · see citing works
“IMiDs are already clinically approved drugs, and PROTACs are currently undergoing clinical trials (Mullard, 2019).”
BackgroundSelective Degradation of GSPT1 by Cereblon Modulators Identified via a Focused Combinatorial Library
Powell, C. E., Du, G., Che, J., He, Z., Donovan, K. A., Yue, H., Wang, E. S., Nowak, R. P., Zhang, T., Fischer, E. S., et al. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00520 · Cited by 88 · see citing works
Site-Specific Labeling of Endogenous Proteins Using CoLDR Chemistry
Reddi, R. N., Rogel, A., Resnick, E., Gabizon, R., Prasad, P. K., Gurwicz, N., Barr, H. M., Shulman, Z., & London, N. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c06167 · Cited by 84 · see citing works
Discovery of a Highly Potent and Selective Dual PROTAC Degrader of CDK12 and CDK13
Yang, J., Chang, Y., Tien, J. C.-Y., Wang, Z., Zhou, Y., Zhang, P., Huang, W., Vo, J. N., Apel, I. J., Wang, C., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00384 · Cited by 96 · see citing works
RIBOTACs: Small Molecules Target RNA for Degradation
Dey, S. K., & Jaffrey, S. R. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.07.015 · Cited by 82 · see citing works
Progress and Challenges in Targeted Protein Degradation for Neurodegenerative Disease Therapy
Fang, Y., Wang, J., Zhao, M., Zheng, Q., Ren, C., Wang, Y., & Zhang, J. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00844 · Cited by 100 · see citing works
Ubiquitin ligases in cancer: Functions and clinical potentials
Duan, S., & Pagano, M. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.04.008 · Cited by 73 · see citing works
Strategies for the discovery of oral PROTAC degraders aimed at cancer therapy
Han, X., & Sun, Y. (2022) · Cell Reports Physical Science · doi:10.1016/j.xcrp.2022.101062 · Cited by 89 · see citing works
Disch, J. S., Duffy, J. M., Lee, E. C. Y., Gikunju, D., Chan, B., Levin, B. D., Monteiro, M. I., Talcott, S. A., Lau, A. C., Zhou, F., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00127 · Cited by 72 · see citing works
Assays and Technologies for Developing Proteolysis Targeting Chimera Degraders
Liu, X., Zhang, X., Lv, D., Yuan, Y., Zheng, G., & Zhou, D. (2020) · Future Medicinal Chemistry · doi:10.4155/fmc-2020-0073 · Cited by 73 · see citing works
“(CT, USA) [18,19] is a milestone in the field of PROTAC-mediated target protein degradation, propelling a fast-growing PROTAC field in the coming years.”
BackgroundInfluentialClickRNA-PROTAC for Tumor-Selective Protein Degradation and Targeted Cancer Therapy
Teng, X., Zhao, X., Dai, Y., Zhang, X., Zhang, Q., Wu, Y., Hu, D., & Li, J. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.4c06402 · Cited by 69 · 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
“Currently, several orally administered PROTAC drugs are in clinical trials for cancer treatment [19, 21, 22, 118, 119].”
BackgroundTargeted deubiquitination rescues distinct trafficking-deficient ion channelopathies
Kanner, S. A., Shuja, Z., Choudhury, P., Jain, A., & Colecraft, H. M. (2020) · Nature Methods · doi:10.1038/s41592-020-00992-6 · Cited by 63 · 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
Targeting androgen receptor degradation with PROTACs from bench to bedside
Jia, X., & Han, X. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.114112 · Cited by 67 · see citing works
Discovery of Novel PDEδ Degraders for the Treatment of KRAS Mutant Colorectal Cancer
Cheng, J., Li, Y., Wang, X., Dong, G., & Sheng, C. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00929 · Cited by 67 · see citing works
Bhela, I. P., Ranza, A., Balestrero, F. C., Serafini, M. T., Aprile, S., Martino, R. M. C. D., Condorelli, F., & Pirali, T. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01218 · Cited by 67 · see citing works
Comprehensive Landscape of Active Deubiquitinating Enzymes Profiled by Advanced Chemoproteomics
Pinto-Fernández, A., Davis, S. A., Schofield, A. B., Scott, H. C., Zhang, P., Salah, E., Mathea, S., Charles, P. D., Damianou, A., Bond, G. L., et al. (2019) · Frontiers in Chemistry · doi:10.3389/fchem.2019.00592 · Cited by 61 · see citing works
“, 2019), which, in addition to PROteolysis-TArgeting chimeras (PROTACS) (Mullard, 2019), are paving the way to explore the Ub system in drug discovery development programs by modulating the turnover of key targets in the context of cancer, dementia, and inflammation (Pinto-Fernandez and Kessler, 2016; Harrigan et al.”
BackgroundSiepe, D. H., Picton, L. K., & García, K. C. (2023) · ACS Synthetic Biology · doi:10.1021/acssynbio.2c00587 · Cited by 61 · see citing works
“While classical 54 degraders have been successful (Mullard, 2019), this approach is ultimately limited to cytosolic 55 targets and therefore 1/3 of the protein-coding genes representing the membrane proteome is not 56 accessible by this approach (Thul et al.”
AKT kinases as therapeutic targets
Hassan, D., Menges, C. W., Testa, J. R., & Bellacosa, A. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-024-03207-4 · Cited by 68 · see citing works
“…of their biodistribution, off-target systemic toxicity, difficulty finding suitable ligands for the protein of interest [369], as well as their large molecular weights, which impede their cell membrane traversal and concentration in tissues, resulting in reduced target occupancy [370].”
The Promise and Current Status of CDK12/13 Inhibition for the Treatment of Cancer
Tadesse, S., Duckett, D. R., & Monastyrskyi, A. (2020) · Future Medicinal Chemistry · doi:10.4155/fmc-2020-0240 · Cited by 57 · see citing works
E3 ligase ligand optimization of Clinical PROTACs
Jiang, H., Xiong, H., Gu, S.-X., & Wang, M. (2023) · Frontiers in Chemistry · doi:10.3389/fchem.2023.1098331 · Cited by 61 · see citing works
“Arvinas is the first company to clinically implement two PROTAC degraders, the androgen receptor (AR) degrader ARV-110 and the estrogen receptor (ER) degrader ARV-471 (Mullard, 2019).”
BackgroundInfluentialDrug design targeting active posttranslational modification protein isoforms
Meng, F., Liang, Z. T., Zhao, K., & Luo, C. (2020) · Medicinal Research Reviews · doi:10.1002/med.21774 · Cited by 56 · see citing works
“Recently, two protein degradation drugs ARV‐110 and ARV‐471 derived from PROTAC have been approved for clinical studies for metastatic castration‐resistant prostate cancer.(243)”
BackgroundApplications of Bacterial Degrons and Degraders — Toward Targeted Protein Degradation in Bacteria
Izert, M. A., Klimecka, M. M., & Górna, M. W. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.669762 · Cited by 47 · see citing works
“In 2019, the first PROTAC was approved for clinical trials in prostate cancer treatment (Mullard, 2019) and more degraders are soon going to be tested in patients (Mullard, 2021).”
BackgroundZhang, J., Che, J., Luo, X., Wu, M., Kan, W., Jin, Y., Wang, H., Pang, A., Li, C., Huang, W., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00324 · Cited by 63 · see citing works
Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One
Salerno, A., Seghetti, F., Caciolla, J., Uliassi, E., Testi, E., Guardigni, M., Roberti, M., Milelli, A., & Bolognesi, M. L. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00302 · Cited by 55 · see citing works
Polyubiquitin Chains Linked by Lysine Residue 48 (K48) Selectively Target Oxidized Proteins In Vivo
Manohar, S., Jacob, S., Wang, J., Wiechecki, K., Koh, H. W. L., Simões, V., Choi, H., Vogel, C., & Silva, G. M. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7826 · Cited by 50 · see citing works
“Given the recent development and clinical use of bifunctional drugs that direct specific protein targets for ubiquitin-mediated proteolysis (13, 48), the ability to identify proteins that, when cleared, increase cell viability and specifically direct them to the proteasome using small molecules presents an attractive…”
BackgroundPotential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges
Ye, P., Chi, X., Cha, J., Luo, S., Yang, G., Yan, X., & Yang, W. (2021) · Cells · doi:10.3390/cells10123309 · Cited by 49 · see citing works
Beketova, E., Fang, S., Owens, J. L., Liu, S., Chen, X., Zhang, Q., Asberry, A. M., Deng, X., Malola, J., Huang, J., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-1228 · Cited by 44 · see citing works
“One of the AR degraders utilizing PROTAC technology is in a phase I clinical trial (51).”
MethodChabanon, R. M., Morel, D., & Postel-Vinay, S. C. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.09.018 · Cited by 43 · see citing works
P-TEFb as A Promising Therapeutic Target
Fujinaga, K. (2020) · Molecules · doi:10.3390/molecules25040838 · Cited by 43 · see citing works
Small-Molecule Degraders beyond PROTACs—Challenges and Opportunities
Kastl, J. M., Davies, G., Godsman, E., & Holdgate, G. A. (2021) · SLAS Discovery · doi:10.1177/2472555221991104 · Cited by 43 · see citing works
Potjewyd, F., & Axtman, A. D. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.768655 · Cited by 39 · see citing works
“PROTACs have recently proven effective in the clinic with androgen and estrogen receptor targeting PROTACs for cancer (Mullard, 2019).”
BackgroundRej, R. K., Allu, S. R., Roy, J., Acharyya, R. K., Kiran, I. N. C., Addepalli, Y., & Dhamodharan, V. (2024) · Pharmaceuticals · doi:10.3390/ph17040494 · Cited by 42 · see citing works
Clearance of plasma PCSK9 via the asialoglycoprotein receptor mediated by heterobifunctional ligands
Bagdanoff, J. T., Smith, T. M., Allan, M., O’Donnell, P. H., Nguyen, Z., Moore, E. A., Baird, J., Wang, S., Subramanian, V., Tigani, B., et al. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2022.12.003 · Cited by 40 · see citing works
Exploiting E3 ubiquitin ligases to reeducate the tumor microenvironment for cancer therapy
Li, X.-M., Zhao, Z., Xiao, Y., Xia, Q., Zhou, P., Wang, S., Wu, H., & Hu, J. (2023) · Experimental Hematology and Oncology · doi:10.1186/s40164-023-00394-2 · Cited by 38 · see citing works
Zhang, C., Ötjengerdes, R., Roewe, J., Mejı́as, R., & Marschall, A. L. J. (2020) · BioDrugs · doi:10.1007/s40259-020-00419-w · Cited by 40 · see citing works
“Proteolysis-targeting chimaeras (PROTACs), which are bispecific binders, have recently gained much attention, with the first one reaching clinical studies [112, 113].”
BackgroundHung, C.-L., Liu, H.-H., Fu, C., Yeh, H.-H., Hu, T.-L., Kuo, Z., Lin, Y.-C., Jhang, M.-R., Hwang, C.-S., Hsu, H., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104500 · Cited by 39 · see citing works
“These compounds either by employing cere-blon (CRBN)- (ARV-110, TD-802, ARD-2128) or von Hippel-Lindau (VHL)- (ARCC4, ARD-266, ARD-69, ARD-61) mediated degradation, effectively inhibit tumor proliferation in both androgen-dependent as well as CRPC models.”
Regulation of large and small G proteins by ubiquitination
Dohlman, H. G., & Campbell, S. L. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.rev119.011068 · Cited by 35 · see citing works
“This novel technology has led to first ‘degrading’ drug that is targeted to the androgen receptor for prostate cancer treatment, and is now in phase 1 clinical trials [reviewed in (98,99)].”
BackgroundPROTAC: targeted drug strategy. Principles and limitations
Koroleva, O. A., Dutikova, Y. V., Trubnikov, A. V., Zenov, F. A., Manasova, E. V., Shtil, A. A., & Kurkin, A. V. (2022) · Russian Chemical Bulletin · doi:10.1007/s11172-022-3659-z · Cited by 38 · see citing works
Application of Negative Design To Design a More Desirable Virtual Screening Library
Yang, Z., He, J.-H., Lü, A., Hou, T., & Cao, D. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01476 · Cited by 29 · see citing works
Targeted Protein Degradation: The New Frontier of Antimicrobial Discovery?
Powell, M., Blaskovich, M. A. T., & Hansford, K. A. (2021) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.1c00203 · Cited by 28 · see citing works
Li, X.-M., Wu, H., Xia, Q., Zhou, P., Wang, S., Xiao, Y., & Hu, J. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112882 · Cited by 29 · see citing works
Photopharmacology of Proteolysis-Targeting Chimeras: A New Frontier for Drug Discovery
Zeng, S., Zhang, H., Shen, Z., & Huang, W. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.639176 · Cited by 27 · see citing works
“, 2020), and, in 2019, two oral PROTACs, ARV-471 (NCT04072952) and ARV-110 (NCT03888612), have advanced into clinical trials for the treatment of metastatic breast cancer and prostate cancer, respectively (Mullard, 2019; Wang Y. et al., 2020).”
BackgroundAl‐Ghabkari, A., Huang, B., & Park, M. (2024) · Cells · doi:10.3390/cells13030218 · Cited by 27 · see citing works
“In 2019 and 2020, clinical trials of PROTACs were established for two cancer targets: estrogen (ER) and androgen (AR) receptors [141,142].”
BackgroundThe Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents
Coll-Martínez, B., Delgado, A., & Crosas, B. (2020) · Molecules · doi:10.3390/molecules25245956 · Cited by 27 · see citing works
A Leucine-Rich Repeat Protein Provides a SHOC2 the RAS Circuit: a Structure-Function Perspective
Kwon, J. J., & Hahn, W. C. (2021) · Molecular and Cellular Biology · doi:10.1128/mcb.00627-20 · Cited by 25 · see citing works
Stephens, E. A., Ludwicki, M. B., Meksiriporn, B., Li, M., Ye, T., Monticello, C., Forsythe, K. J., Kummer, L., Zhou, P., Plückthun, A., et al. (2021) · ACS Synthetic Biology · doi:10.1021/acssynbio.1c00357 · Cited by 27 · see citing works
Wortmann, L., Lindenthal, B., Muhn, P., Walter, A., Nubbemeyer, R., Heldmann, D., Sobek, L., Morandi, F., Schrey, A. K., Moosmayer, D., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01382 · Cited by 23 · see citing works
Ubiquitination, Biotech Startups, and the Future of TRIM Family Proteins: A TRIM-Endous Opportunity
Bhaduri, U., & Merla, G. (2021) · Cells · doi:10.3390/cells10051015 · Cited by 25 · see citing works
“Meanwhile, in 2019, for the first time, PROTAC degraders ARV-110 and ARV-471 entered phase 1 clinical trials for the treatment of prostate cancer and breast cancer, respectively [18].”
BackgroundRecent Progress in DNA Damage Response-Targeting PROTAC Degraders
Cheng, B., Fei, X., Ding, Z., Peng, X., Su, Z., Pan, W., & Chen, J. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00015 · Cited by 27 · see citing works
Targeted protein degradation in antibacterial drug discovery?
Gopal, P., & Dick, T. (2019) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2019.11.005 · Cited by 24 · see citing works
“…Lab in 2008, which could bind and induce degradation of the androgen receptor (AR) to the first PROTAC molecule (ARV-110) to enter the clinic with a Phase I trial for prostate cancer earlier this year, this field has rapidly grown and gained attention from the scientific community (Mullard, 2019).”
BackgroundStructure driven compound optimization in targeted protein degradation
Leissing, T. M., Luh, L. M., & Cromm, P. M. (2020) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2020.11.005 · Cited by 21 · see citing works
Reversible Covalent PROTACs: Novel and Efficient Targeted Degradation Strategy
Yuan, M., Chu, Y., & Duan, Y. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.691093 · Cited by 27 · see citing works
“This drug design strategy has increasingly attracted attention, especially upon the first PROTAC entering clinical trials in 2019 (Mullard, 2019).”
BackgroundElectrophilic Natural Products as Drug Discovery Tools
Gehrtz, P., & London, N. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.03.008 · Cited by 24 · see citing works
Design of PROTACs utilizing the E3 ligase GID4 for targeted protein degradation
Li, Y., Bao, K., Sun, J., Ge, R., Zhang, Q., Zhang, B., Yan, X., Li, J., Shi, F., Zhang, M., et al. (2025) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01537-1 · Cited by 24 · see citing works
“Here we show that the E3 ligase GID4 (glucose-induced degradation deficient complex 4) can be leveraged for targeted protein degradation using a noncovalent small molecule.”
Manda, S., Lee, N. K., Oh, D., & Lee, J. (2020) · Molecules · doi:10.3390/molecules25081948 · Cited by 22 · see citing works
Cui, Q., Huang, C., Liu, J., & Zhang, J. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c01130 · Cited by 23 · see citing works
Targeted Protein Degradation: An Emerging Therapeutic Strategy in Cancer
Barghout, S. H. (2020) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/1871520620666200410082652 · Cited by 21 · see citing works
Development of DNA Aptamer-Based PROTACs That Degrade the Estrogen Receptor
Tsujimura, H., Naganuma, M., Ohoka, N., Inoué, T., Naito, M., Tsuji, G., & Demizu, Y. (2023) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.3c00126 · Cited by 24 · see citing works
Wang, Y., Wei, T., Zhao, M., Huang, A., Sun, F., Chen, L., Lin, R., Xie, Y., Zhang, M., Xu, S., et al. (2024) · PLoS Biology · doi:10.1371/journal.pbio.3002550 · Cited by 23 · see citing works
Induced proximity at the cell surface
Till, N. A., Ramanathan, M., & Bertozzi, C. R. (2025) · Nature Biotechnology · doi:10.1038/s41587-025-02592-1 · Cited by 21 · see citing works
“PROTACs and molecular glues were the original launch point of the TPD field, and several such molecules are undergoing clinical evaluation 13,14 .”
Synthetic biology approaches for targeted protein degradation
Chen, R. P., Gaynor, A. S., & Chen, W. (2019) · Biotechnology Advances · doi:10.1016/j.biotechadv.2019.107446 · Cited by 18 · see citing works
“However, their ease of delivery makes them a powerful drug treatment option, and PROTACS have begun to enter clinical trials this year (Mullard, 2019).”
BackgroundTernary complex dissociation kinetics contribute to mutant-selective EGFR degradation
Rosenberg, S., Shanahan, F., Yamazoe, S., Kschonsak, M., Zeng, Y. J., Lee, J., Plise, E. G., Yen, I., Rose, C. M., Quinn, J. G., et al. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.01.007 · Cited by 18 · see citing works
He, X., Zeng, S., Wen, Y., Yang, T., Huang, C., Li, Y.-F., Zhang, Z., Ding, K., Liu, T., Tan, Y., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.4c18083 · Cited by 18 · see citing works
Proteostasis Dysregulation in Pancreatic Cancer
Arpalahti, L., Haglund, C., & Holmberg, C. I. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-38266-7_4 · Cited by 17 · see citing works
Molecular basis and dual ligand regulation of tetrameric estrogen receptor α/14-3-3ζ protein complex
Somsen, B. A., Sijbesma, E., Leysen, S., Honzejková, K., Visser, E. J., Cossar, P. J., Obšil, T., Brunsveld, L., & Ottmann, C. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104855 · Cited by 17 · see citing works
New Targets and Emergent Therapies for Osteoporosis
Brommage, R. (2019) · Handbook of experimental pharmacology · doi:10.1007/164_2019_329 · Cited by 18 · see citing works
Monovalent protein-degraders – Insights and future perspectives
Cornella‐Taracido, I., & Garcı́a-Echeverrı́a, C. (2020) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2020.127202 · Cited by 18 · see citing works
Photoactive Bifunctional Degraders: Precision Tools To Regulate Protein Stability
Kounde, C. S., & Tate, E. W. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01542 · Cited by 17 · see citing works
- Authors
- Mullard, A.
- Corresponding author
- Mullard, Asher
- Venue
- Nature Reviews Drug Discovery
- Published
- 2019-03-06
- Volume
- 18
- Issue
- 4
- Pages
- 237-239
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- OpenAlex
- W2920736663
- Cited by
- 146
- References
- 0
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 15 · 2023: 18 · 2022: 16 · 2021: 28 · 2020: 32 · 2019: 20
- Type
- other
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- targeted protein degradation, PROTACs, clinical trials, protein degraders, anticancer agents, E3 ubiquitin ligase, drug development
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
