Cited by 245Protein Degradation and InhibitorsChemical Synthesis and AnalysisRNA Interference and Gene Delivery

The DOI matches its Crossref record; 52 of the 53 references it cites were found in a registry or an index.

Bifunctional small molecules that mediate the degradation of extracellular proteins

Open access

Caianiello, David F., Zhang, Mengwen, Ray, Jason D., Howell, Rebecca A., Swartzel, Jake C., Branham, Emily M. J., Chirkin, Egor, Sabbasani, Venkata R., Gong, Angela Z., McDonald, David M., Muthusamy, Viswanathan, Spiegel, David A.·2021·Nature Chemical Biology

DOI 10.1038/s41589-021-00851-1

Published version of a preprint

Open this paper in CoChat — free account Open PDF

Abstract

Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy. Most TPD technologies use the ubiquitin-proteasome system, and are therefore limited to targeting intracellular proteins. To address this limitation, we developed a class of modular, bifunctional synthetic molecules called MoDE-As (molecular degraders of extracellular proteins through the asialoglycoprotein receptor (ASGPR)), which mediate the degradation of extracellular proteins. MoDE-A molecules mediate the formation of a ternary complex between a target protein and ASGPR on hepatocytes. The target protein is then endocytosed and degraded by lysosomal proteases. We demonstrated the modularity of the MoDE-A technology by synthesizing molecules that induce depletion of both antibody and proinflammatory cytokine proteins. These data show experimental evidence that nonproteinogenic, synthetic molecules can enable TPD of extracellular proteins in vitro and in vivo. We believe that TPD mediated by the MoDE-A technology will have widespread applications for disease treatment.

Integrity signals

Registry

Crossref · 10.1038/s41589-021-00851-1

Cites

52 of 52 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

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?

TNF biology, pathogenic mechanisms and emerging therapeutic strategies
Kalliolias, G. D., & Ivashkiv, L. B. (2015) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2015.169 · Cited by 1,453
Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms
Akinc, A., Querbes, W., De, S., Qin, J., Frank-Kamenetsky, M., Jayaprakash, K. N., Jayaraman, M., Rajeev, K. G., Cantley, W. L., Dorkin, J. R., et al. (2010) · Molecular Therapy · doi:10.1038/mt.2010.85 · Cited by 1,261
Lysosome-targeting chimaeras for degradation of extracellular proteins
Banik, S. M., Pedram, K., Wisnovsky, S., Ahn, G., Riley, N. M., & Bertozzi, C. R. (2020) · Nature · doi:10.1038/s41586-020-2545-9 · Cited by 1,199
PROTACs: great opportunities for academia and industry
Sun, X., Gao, H., Yang, Y., He, M., Wu, Y., Song, Y.-G., Tong, Y., & Rao, Y. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0101-6 · Cited by 663
Asialoglycoprotein receptor mediated hepatocyte targeting — Strategies and applications
D’souza, A. A., & Devarajan, P. V. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.02.022 · Cited by 637
Development of Antibody-Based PROTACs for the Degradation of the Cell-Surface Immune Checkpoint Protein PD-L1
Cotton, A. D., Nguyen, D. P., Gramespacher, J. A., Seiple, I. B., & Wells, J. A. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.0c10008 · Cited by 551
The galactose-specific recognition system of mammalian liver: The route of ligand internalization in rat hepatocytes
Wall, D. A., Wilson, G., & Hubbard, A. L. (1980) · Cell · doi:10.1016/0092-8674(80)90116-6 · Cited by 484
A Comprehensive Mathematical Model for Three-Body Binding Equilibria
Douglass, E. F., Miller, C. J., Sparer, G., Shapiro, H., & Spiegel, D. A. (2013) · Journal of the American Chemical Society · doi:10.1021/ja311795d · Cited by 472
Self-citation
The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling
Grozovsky, R., Begonja, A. J., Liu, K., Visner, G. A., Hartwig, J. H., Falet, H., & Hoffmeister, K. M. (2014) · Nature Medicine · doi:10.1038/nm.3770 · Cited by 360
Galactose and N-acetylgalactosamine-specific endocytosis of glycopeptides by isolated rat hepatocytes
Baenziger, J., & Fiete, D. (1980) · Cell · doi:10.1016/0092-8674(80)90371-2 · Cited by 248

Show all 53 references

Research works printed but not linked: 2

Spiegel, D. A., Caianiello, D. & Zhang, M. Bifunctional small molecules to target the selective degradation of circulating proteins. PCT patent WO 2019/199634. US patent US62/655,055 US62/788,040 (2019).
Jevsevar, S. & Kunstelj, M. in Therapeutic Proteins: Strategies to Modulate Their Plasma Half-lives (ed. Kontermann, R.) Ch. 3 (Wiley-Blackwell, 2012).

Sorted by citations

Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396
Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs
Alabi, S. B., & Crews, C. M. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100647 · Cited by 279
Modular cytokine receptor-targeting chimeras for targeted degradation of cell surface and extracellular proteins
Pance, 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
Development of Triantennary N‑Acetylgalactosamine Conjugates as Degraders for Extracellular Proteins
Zhou, Y., Teng, P., Montgomery, N. T., Li, X., & Tang, W. (2021) · ACS Central Science · doi:10.1021/acscentsci.1c00146 · Cited by 231
Targeted protein degradation for cancer therapy
Hinterndorfer, M., Spiteri, V. A., Ciulli, A., & Winter, G. E. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-025-00817-8 · Cited by 263
Proximity-Based Modalities for Biology and Medicine
Liu, X., & Ciulli, A. (2023) · ACS Central Science · doi:10.1021/acscentsci.3c00395 · Cited by 206
Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras
Ahn, 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 199
Transferrin receptor targeting chimeras for membrane protein degradation
Zhang, D., Duque-Jimenez, J., Facchinetti, F., Brixi, G., Rhee, K., Feng, W. W., Janne, P. A., & Zhou, X. X. (2024) · Nature · doi:10.1038/s41586-024-07947-3 · Cited by 210
Extracellular targeted protein degradation: an emerging modality for drug discovery
Wells, J. A., & Kumru, K. S. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00833-z · Cited by 202
Bifunctional Compounds as Molecular Degraders for Integrin-Facilitated Targeted Protein Degradation
Zheng, J., He, W., Li, J., Feng, X., Li, Y., Cheng, B., Zhou, Y., Li, M., Liu, K., Shao, X., et al. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c08367 · Cited by 175
Emerging degrader technologies engaging lysosomal pathways
Ding, Y., Xing, D., Fei, Y., & Lu, B. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00624c · Cited by 165
Aptamer‐LYTACs for Targeted Degradation of Extracellular and Membrane Proteins
Wu, Y., Lin, B., Lu, Y., Li, L., Deng, K., Zhang, S., Zhang, H., Yang, C. J., & Zhu, Z. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202218106 · Cited by 147
Glycomimetics for the inhibition and modulation of lectins
Leusmann, S., Ménová, P., Shanina, E., Titz, A., & Rademacher, C. (2023) · Chemical Society Reviews · doi:10.1039/d2cs00954d · Cited by 139
Targeted Protein Degradation via Lysosomes
Paudel, R. R., Lu, D., Chowdhury, S. R., Monroy, E. Y., & Wang, J. (2022) · Biochemistry · doi:10.1021/acs.biochem.2c00310 · Cited by 121
Targeted protein degradation directly engaging lysosomes or proteasomes
Kim, J., Byun, I., Kim, D. Y., Joh, H., Kim, H. J., & Lee, M. J. (2024) · Chemical Society Reviews · doi:10.1039/d3cs00344b · Cited by 108
Targeting the undruggables—the power of protein degraders
Zhang, C., Liu, Y., Li, G., Yang, Z., Han, C., Sun, X., Sheng, C., Ding, K., & Rao, Y. (2024) · 中国科学通报：英文版 · doi:10.1016/j.scib.2024.03.056 · Cited by 112
Glycobiology of rheumatic diseases
Kissel, T., Toes, R. E. M., Huizinga, T. W. J., & Wuhrer, M. (2022) · Nature Reviews Rheumatology · doi:10.1038/s41584-022-00867-4 · Cited by 108
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 102
Degradation from the outside in: Targeting extracellular and membrane proteins for degradation through the endolysosomal pathway
Ahn, G., Banik, S. M., & Bertozzi, C. R. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.02.024 · Cited by 98
Insulin-like Growth Factor 2 (IGF2)-Fused Lysosomal Targeting Chimeras for Degradation of Extracellular and Membrane Proteins
Zhang, B., Brahma, R. K., Zhu, L., Feng, J., Hu, S., Qian, L., Du, S., Yao, S. Q., & Ge, J. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c08886 · Cited by 88
Dendronized DNA Chimeras Harness Scavenger Receptors To Degrade Cell Membrane Proteins
Zhu, C., Wang, W., Wang, Y., Zhang, Y., & Li, J. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202300694 · Cited by 88
DNA-encoded library-enabled discovery of proximity-inducing small molecules
Mason, J. W., Chow, Y. T., Hudson, L., Tutter, A., Michaud, G., Westphal, M. V., Shu, W., Ma, X., Tan, Z. Y., Coley, C. W., et al. (2024) · Nature Chemical Biology · doi:10.1038/s41589-023-01458-4 · Cited by 83
Development of folate receptor targeting chimeras for cancer selective degradation of extracellular proteins
Zhou, Y., Li, C., Chen, X., Zhao, Y., Liao, Y., Huang, P., Wu, W., Nieto, N. S., Li, L., & Tang, W. (2024) · Nature Communications · doi:10.1038/s41467-024-52685-9 · Cited by 99
Cell Membrane as A Promising Therapeutic Target: From Materials Design to Biomedical Applications
Wu, X., Hu, J., & Yoon, J. (2024) · Angewandte Chemie International Edition · doi:10.1002/anie.202400249 · Cited by 79
Antiviral PROTACs: Opportunity borne with challenge
Liang, J., Wu, Y., Lan, K., Dong, C., Wu, S., Li, S., & Zhou, H. (2023) · Cell Insight · doi:10.1016/j.cellin.2023.100092 · Cited by 76
A Bifunctional Lysosome‐Targeting Chimera Nanoplatform for Tumor‐Selective Protein Degradation and Enhanced Cancer Immunotherapy
Xing, Y., Li, J., Wang, L., Zhu, Z., Yan, J., Liu, Y., & Liu, Q. (2025) · Advanced Materials · doi:10.1002/adma.202417942 · Cited by 76
Harnessing the Lysosomal Sorting Signals of the Cation-Independent Mannose-6-Phosphate Receptor for Targeted Degradation of Membrane Proteins
Yu, J., Li, H., Fang, T., Yun, C., Liu, X., Xu, J., Jiang, X., & Cai, X. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c07687 · Cited by 72
Opportunities and challenges of protein-based targeted protein degradation
Shen, F., & Dassama, L. M. K. (2023) · Chemical Science · doi:10.1039/d3sc02361c · Cited by 70
Targeted protein degradation in cancers: Orthodox PROTACs and beyond
Li, J., Chen, X., Lü, A., & Liang, C. (2023) · The Innovation · doi:10.1016/j.xinn.2023.100413 · Cited by 68
Molecular glue-mediated targeted protein degradation: A novel strategy in small-molecule drug development
Tan, X., Huang, Z., Pei, H., Jia, Z., & Zheng, J. (2024) · iScience · doi:10.1016/j.isci.2024.110712 · Cited by 66
Beyond Proteolysis-Targeting Chimeric Molecules: Designing Heterobifunctional Molecules Based on Functional Effectors
Hua, L., Zhang, Q., Zhu, X., Wang, R., You, Q., & Wang, L. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00316 · Cited by 69
A co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation
Wang, Q., Yang, X., Yuan, R., Shen, A., Wang, P., Li, H., Zhang, J., Tian, C., Jiang, Z., Li, W., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46130-0 · Cited by 72
Nano‐LYTACs for Degradation of Membrane Proteins and Inhibition of CD24/Siglec‐10 Signaling Pathway
Wang, K., Yu, A., Liu, K., Feng, C., Hou, Y., Chen, J., Ma, S., Huang, L., & Dai, X. (2023) · Advanced Science · doi:10.1002/advs.202300288 · Cited by 59
Biomarker-activated multifunctional lysosome-targeting chimeras mediated selective degradation of extracellular amyloid fibrils
Liu, Z., Deng, Q., Qin, G., Yang, J., Zhang, H., Ren, J., & Qu, X. (2023) · Chem · doi:10.1016/j.chempr.2023.06.003 · Cited by 59
Targeted degradation of extracellular secreted and membrane proteins
Chen, X., Zhou, Y., Zhao, Y., & Tang, W. (2023) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2023.08.013 · Cited by 59
Novel approaches to targeted protein degradation technologies in drug discovery
Xue, Y., Bolinger, A. A., & Zhou, J. (2023) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2023.2187777 · Cited by 59
Expanding the horizons of targeted protein degradation: A non-small molecule perspective
Huang, X., Wu, F., Ye, J., Wang, L., Wang, X., Li, X., & He, G. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.01.010 · Cited by 62
Non-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope
Ma, S., Ji, J., Tong, Y., Zhu, Y., Dou, J., Zhang, X., Xu, S., Zhu, T., Xu, X., You, Q., et al. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.02.022 · Cited by 59
Hepatocyte targeting via the asialoglycoprotein receptor
Ramírez-Cortés, F., & Ménová, P. (2025) · RSC Medicinal Chemistry · doi:10.1039/d4md00652f · Cited by 55
Surface engineering of nanoparticles for precision medicine
Zheng, J., Sun, Y., Shen, Y., & Zhou, Z. (2025) · Precision medicine and engineering. · doi:10.1016/j.preme.2025.100037 · Cited by 55
Emerging targeted protein degradation tools for innovative drug discovery: From classical PROTACs to the novel and beyond
Zhong, Y., Chi, F., Wu, H., Liu, Y., Xie, Z., Huang, W., Shi, W., & Qian, H. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114142 · Cited by 52
Deficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress
Zhang, Z., Leng, X., Zhai, Y. Y., Zhang, X. L., Sun, Z. W., Xiao, J. Y., Lu, J. F., Liu, K., Xia, B., Gao, Q., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46135-9 · Cited by 58
Site-Specific Chemoenzymatic Conjugation of High-Affinity M6P Glycan Ligands to Antibodies for Targeted Protein Degradation
Zhang, X., Liu, H., He, J., Ou, C., Donahue, T. C., Muthana, M. M., Su, L., & Wang, L. (2022) · ACS Chemical Biology · doi:10.1021/acschembio.1c00751 · Cited by 48
Targeted Lysosomal Degradation of Secreted and Cell Surface Proteins through the LRP-1 Pathway
Loppinet, E., Besser, H. A., Lee, C. E., Zhang, W., Cui, B., & Khosla, C. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c05109 · Cited by 48
Engineered platelets as targeted protein degraders and application to breast cancer models
Chen, Y., Pal, S., Li, W., Liu, F., Yuan, S., & Hu, Q. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02494-8 · Cited by 49
Application of Novel Degraders Employing Autophagy for Expediting Medicinal Research
Li, X., Liu, Q., Xie, X., Peng, C., Pang, Q., Liu, B., & Han, B. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01712 · Cited by 46
Advancement of drugs conjugated with GalNAc in the targeted delivery to hepatocytes based on asialoglycoprotein receptor
Zhang, Y., Liu, H., Zhen, W., Jiang, T., & Cui, J. (2025) · Carbohydrate Research · doi:10.1016/j.carres.2025.109426 · Cited by 48
Proximity-inducing modalities: the past, present, and future
Singh, S., Tian, W., Severance, Z. C., Chaudhary, S. K., Anokhina, V. S., Mondal, B., Pergu, R., Singh, P. R., Dhawa, U., Singha, S., et al. (2023) · Chemical Society Reviews · doi:10.1039/d2cs00943a · Cited by 47
Directed evolution of genetically encoded LYTACs for cell-mediated delivery
Yang, J. L., Yamada‐Hunter, S. A., Labanieh, L., Sotillo, E., Cheah, J. S., Roberts, D. S., Mackall, C. L., Bertozzi, C. R., & Ting, A. Y. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2320053121 · Cited by 45
Nanoparticle‐Mediated Targeted Protein Degradation: An Emerging Therapeutics Technology
Baker, A., Ho, A. P. T., Itzhaki, L. S., & Fruk, L. (2025) · Angewandte Chemie International Edition · doi:10.1002/anie.202503958 · Cited by 44
Polyvalent folate receptor-targeting chimeras for degradation of membrane proteins
Xiao, D., Dong, J., Xie, F., Feng, X., Wang, J., Xu, X., Tang, B., Sun, C., Wang, Y., Zhong, W., et al. (2025) · Nature Chemical Biology · doi:10.1038/s41589-025-01924-1 · Cited by 54
Extracellular protein homeostasis in neurodegenerative diseases
Wilson, M. R., Satapathy, S., & Vendruscolo, M. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00786-2 · Cited by 43
The application of PROTAC in HDAC
Chen, S., Zheng, Y., Liang, B., Yin, Y., Yao, J., Wang, Q., Liu, Y., & Neamati, N. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115746 · Cited by 45
PROTACS: A technology with a gold rush-like atmosphere
Wang, Y., Lan, L., Wang, M., Zhang, J., Gao, Y., Shi, L., & Sun, L. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.115037 · Cited by 44
Degradation of Cyclin-Dependent Kinase 9/Cyclin T1 by Optimized Microtubule-Associated Protein 1 Light Chain 3 Beta-Recruiting Coumarin Analogs
Zeng, Y., Xiao, J., Xu, Y., Fan, W., Tian, L., Gao, Y., Chen, Y., & Hu, Y. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00828 · Cited by 43
Induced proximity-based therapeutic modalities
King, E. A., Meyers, M., & Nomura, D. K. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01316-z · Cited by 61
Targeted protein degradation in the transmembrane and extracellular space
Zhu, R., Zhang, H., & Chen, P. R. (2025) · Science · doi:10.1126/science.adx5094 · Cited by 43
Emerging Pharmacotherapeutic Strategies to Overcome Undruggable Proteins in Cancer
Lu, Y., Yang, Y., Zhu, G., Zeng, H., Fan, Y., Guo, F., Xu, D., Wang, B., Chen, D., & Ge, G. (2023) · International Journal of Biological Sciences · doi:10.7150/ijbs.83026 · Cited by 42
Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics
Gupta, Y. A., Savytskyi, O. V., Coban, M., Venugopal, A., Pleqi, V., Weber, C. A., Chitale, R. A., Durvasula, R. V., Hopkins, C. E., Kempaiah, P., et al. (2022) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2022.101151 · Cited by 40
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 42
A plug-and-play monofunctional platform for targeted degradation of extracellular proteins and vesicles
Yao, S., Wang, Y., Tang, Q., Yin, Y., Geng, Y., Xu, L., Liang, S., Xiang, J., Fan, J., Tang, J., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51720-z · Cited by 46
Targeted Protein Degradation Technology and Nanomedicine: Powerful Allies against Cancer
Lin, J., Liu, H., Wu, Y., Jin, J., Zhou, Y., Zhang, H., Nagle, D. G., Chen, H., Zhang, W., & Luan, X. (2023) · Small · doi:10.1002/smll.202207778 · Cited by 38
Bioprobe-RNA-seq-microRaman system for deep tracking of the live single-cell metabolic pathway chemometrics
Gouda, M., Lv, J., Huang, Z., Chen, J., He, Y., & Li, X. (2024) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2024.116504 · Cited by 38
New therapies on the horizon: Targeted protein degradation in neuroscience
Gregory, J. A., Hickey, C. M., Chavez, J. D., & Cacace, A. M. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.08.010 · Cited by 42
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 40
Targeted protein degradation: current molecular targets, localization, and strategies
Pliatsika, D., Blatter, C., & Riedl, R. (2024) · Drug Discovery Today · doi:10.1016/j.drudis.2024.104178 · Cited by 40
Development of Oligomeric Mannose-6-phosphonate Conjugates for Targeted Protein Degradation
Stevens, C. M., Zhou, Y., Teng, P., Rault, L. N., Liao, Y., & Tang, W. (2023) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.2c00479 · Cited by 40
TAC‐tics for Leveraging Proximity Biology in Drug Discovery
Nalawansha, D. A., Mangano, K., den Besten, W., & Potts, P. R. (2023) · ChemBioChem · doi:10.1002/cbic.202300712 · Cited by 36
Targeted degradation of extracellular proteins: state of the art and diversity of degrader designs
Mamun, M. A. A., Bakunts, A. G., & Chernorudskiy, A. L. (2025) · Journal of Hematology & Oncology · doi:10.1186/s13045-025-01703-4 · Cited by 41
Targeted Protein Degradation: Clinical Advances in the Field of Oncology
Salama, A. K. A. A., Trkulja, M. V., Casanova, E., & Uras, I. Z. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315440 · Cited by 36
Methylarginine targeting chimeras for lysosomal degradation of intracellular proteins
Seabrook, L. J., Franco, C. N., Loy, C. A., Osman, J. M., Fredlender, C., Zimak, J., Campos, M., Nguyen, S. T., Watson, R. L., Levine, S. R., et al. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01741-y · Cited by 34
Chemically engineered antibodies for autophagy-based receptor degradation
Cheng, B., Li, M., Zheng, J., Liang, J., Li, Y., Liang, R., Tian, H., Zhou, Z., Ding, L., Ren, J., et al. (2025) · Nature Chemical Biology · doi:10.1038/s41589-024-01803-1 · Cited by 33
Cancer Specific CAIX‐Targeting Supramolecular Lysosome‐Targeting Chimeras (Supra‐LYTAC) for Targeted Protein Degradation
Kim, D., Yang, G., Lim, C., Park, G., Lee, J., Sim, Y., & Ryu, J. (2025) · Advanced Science · doi:10.1002/advs.202503134 · Cited by 30
Biologics-based degraders — an expanding toolkit for targeted-protein degradation
VanDyke, D., Taylor, J. D., Kaeo, K. J., Hunt, J., & Spangler, J. B. (2022) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2022.102807 · Cited by 30
Generation of tau dephosphorylation-targeting chimeras for the treatment of Alzheimer’s disease and related tauopathies
Su, J., Xiao, Y., Wei, L., Lei, H., Sun, F., Wang, W., Yin, J., Xiong, R., Li, S., Zhang, P., et al. (2024) · 中国科学通报：英文版 · doi:10.1016/j.scib.2024.01.019 · Cited by 30
Conjugation with glucagon like peptide-1 enables targeted protein degradation
Zhu, L., Zhou, Y., Zhang, B., Luo, Y., Chen, F., Yan, X., Cai, Y., Jiang, L., & Ge, J. (2023) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2023.106908 · Cited by 30
Biomimetic Nano‐Degrader Based CD47‐SIRPα Immune Checkpoint Inhibition Promotes Macrophage Efferocytosis for Cardiac Repair
Gao, J., Pang, Z., Wang, Q., Tan, Y., Li, Q., Tan, H., Chen, J., Yakufu, W., Wang, Z., Yang, H., et al. (2024) · Advanced Science · doi:10.1002/advs.202306388 · Cited by 28
Targeted degradation of cell surface proteins through endocytosis triggered by cell-penetrating peptide-small molecule conjugates
He, W., Chen, C., Zheng, J., Li, Y., Shi, H., Zhou, Y., Li, M., Gong, P., Liu, K., Shao, X., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-62776-w · Cited by 34
Lysosome-targeting chimeras evolve
Paulk, J. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00835-1 · Cited by 30
Recent advances in induced proximity modalities
Ng, C. S. C., & Banik, S. M. (2022) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2021.102107 · Cited by 27
Desialylated Mesenchymal Stem Cells-Derived Extracellular Vesicles Loaded with Doxorubicin for Targeted Inhibition of Hepatocellular Carcinoma
Yang, C., Guan, Z., Pang, X., Tan, Z., Yang, X., Li, X., & Guan, F. (2022) · Cells · doi:10.3390/cells11172642 · Cited by 28
Synthetic Site-Specific Antibody–Ligand Conjugates Promote Asialoglycoprotein Receptor-Mediated Degradation of Extracellular Human PCSK9
Donahue, T. C., Ou, C., Yang, Q., Flinko, R., Zhang, X., Zong, G., Lewis, G. K., & Wang, L. (2023) · ACS Chemical Biology · doi:10.1021/acschembio.3c00229 · Cited by 32
Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway
Wang, Z., Yuan, L., Liao, X., Guo, X., & Chen, J. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c02143 · Cited by 28
Hijacking Extracellular Targeted Protein Degrader–Drug Conjugates for Enhanced Drug Delivery
Zhao, F., Wu, Y., Schaefer, K., Zhang, Y., Miao, K., Yao, Z. W., Ganjave, S. D., Kumru, K. S., Peters-Clarke, T. M., Inague, A., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c15047 · Cited by 32
IGF2 Peptide-Based LYTACs for Targeted Degradation of Extracellular and Transmembrane Proteins
Mikitiuk, M., Barczyński, J., Bielski, P., Arciniega, M., Tyrcha, U., Hec, A., Lipińska, A. D., Rychłowski, M., Holak, T. A., & Sitar, T. (2023) · Molecules · doi:10.3390/molecules28227519 · Cited by 26
Bifunctional Molecules That Induce Both Targeted Degradation and Transcytosis of Extracellular Proteins in Brain Cells
Howell, R. A., Wang, S., Khambete, M., McDonald, D. M., & Spiegel, D. A. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.3c13320 · Cited by 26
Self-citation
Securing LYTAC with Logic‐Identification System for Cancer Cell‐Selective Membrane Protein Degradation
Fang, Y., Zhang, Y., Bi, S., Peng, B., Wang, C., Ju, H., & Liu, Y. (2024) · Small · doi:10.1002/smll.202310039 · Cited by 27
Recent advances in developing targeted protein degraders
Cheng, B., Li, H., Peng, X., Chen, J., Shao, C., & Kong, Z. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.117212 · Cited by 28
Staudinger Reaction-Responsive Coacervates for Cytosolic Antibody Delivery and TRIM21-Mediated Protein Degradation
Bao, Y., Xu, Z., Cheng, K., Li, X., Chen, F., Yuan, D., Zhang, F., Run-Yu, A., Zeng, X., Zhao, Y., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.4c17054 · Cited by 28
Redefining the Scope of Targeted Protein Degradation: Translational Opportunities in Hijacking the Autophagy–Lysosome Pathway
Cassidy, K. B., & Zhao, H. (2021) · Biochemistry · doi:10.1021/acs.biochem.1c00330 · Cited by 25
Peptide-Mediated Small Molecule Lysosome-Targeting Chimeras for Targeted Degradation of Membrane and Intracellular Proteins
Chen, S., Wang, W., Chen, Z., Li, R., Wu, Z., Dong, G., & Sheng, C. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01449 · Cited by 26
A Self‐Assembling LYTAC Mediates CTGF Degradation and Remodels Inflammatory Tumor Microenvironment for Triple‐Negative Breast Cancer Therapy
Lin, J., Wu, Y., Liang, X., Tang, M., Sun, X., Lu, S., Jin, J., Guo, X., Wang, B., Chen, H., et al. (2025) · Advanced Science · doi:10.1002/advs.202500311 · Cited by 26
Small-Molecule Ligands Targeting Lysosome-Shuttling Receptors and the Emerging Landscape of Lysosome-Targeting Chimeras
Yang, J., & Zhu, H. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c01019 · Cited by 24
Efficient amyloid-β degradation in Alzheimer’s disease using SPYTACs
Teng, F., Liu, J., Cui, T., Tan, X., Liu, K., Hou, Z., (54356), L. Z., Xie, Y., Li, R., Li, D., et al. (2026) · Cell · doi:10.1016/j.cell.2026.01.034 · Cited by 25
Development of Integrin Targeting Chimeras (ITACs) for the Lysosomal Degradation of Extracellular Proteins
Zhou, Y., Liao, Y., Zhao, Y., & Tang, W. (2024) · ChemMedChem · doi:10.1002/cmdc.202300643 · Cited by 22
Discovery of Novel HDAC3 Inhibitors with PD-L1 Downregulating/Degrading and Antitumor Immune Effects
Sun, Z., Xu, C., Cheng, J., Yang, Z., Liu, T., Deng, B., Zhang, X., Peng, X., & Chen, J. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01062 · Cited by 21
Multivalent RGD Peptide-Mediated Nanochimera for Lysosomal Degradation of PDL1 Protein
Song, Y., Cui, L., Liu, Z., Tang, Z., & Chen, X. (2025) · Nano Letters · doi:10.1021/acs.nanolett.5c00341 · Cited by 22
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
Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies
Wolska, A., & Smolewski, P. (2022) · Cancers · doi:10.3390/cancers14153778 · Cited by 21
Targeted protein degradation using the lysosomal pathway
Ghosh, S., Ramadas, B., & Manna, D. (2022) · RSC Medicinal Chemistry · doi:10.1039/d2md00273f · Cited by 22

Authors: Caianiello, D. F., Zhang, M., Ray, J. D., Howell, R. A., Swartzel, J. C., Branham, E. M. J., Chirkin, E., Sabbasani, V. R., Gong, A. Z., McDonald, D. M., Muthusamy, V., & Spiegel, D. A.
Affiliations: Yale University (US)
Corresponding author: Spiegel, David A.
ORCID: Zhang, Mengwen
Ray, Jason D.
Howell, Rebecca A.
Branham, Emily M. J.
Sabbasani, Venkata R.
Gong, Angela Z.
McDonald, David M.
Muthusamy, Viswanathan
Spiegel, David A.
Venue: Nature Chemical Biology
Publisher: Springer Science and Business Media LLC
Published: 2021-08-19
Volume: 17
Issue: 9
Pages: 947-953
ISSN: 1552-4450 (ISSN-L)
1552-4469
DOI: 10.1038/s41589-021-00851-1
OpenAlex: W3195114088
Cited by: 244
References: 53
Citations by year: 2026: 49 · 2025: 62 · 2024: 51 · 2023: 47 · 2022: 28 · 2021: 7
FWCI: 10.51
Type: journal article
Language: en
Open access: green
doi.org
Licence: cc-by-nc-nd
www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Chemical Biology (publishedVersion)
ChemRxiv (acceptedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Royal College of Surgeons in Ireland (submittedVersion)
Funders: U.S. Department of Defense (BC120554)
Yale University
National Institute of General Medical Sciences (T32GM067543)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords: targeted protein degradation, extracellular proteins, asialoglycoprotein receptor, bifunctional small molecules, lysosomal degradation, endocytosis, antibody depletion, inflammatory cytokines, hepatocytes
MeSH terms: Animals, Dinitrophenols, Humans, Male, Mice, Inbred C57BL, Molecular Structure, Asialoglycoprotein Receptor, Mice, Small Molecule Libraries, Hep G2 Cells

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

Bifunctional small molecules that mediate the degradation of extracellular proteins

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks