Bifunctional small molecules that mediate the degradation of extracellular proteins

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.

doi:10.1038/s41589-021-00851-1

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

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. +4 more·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?

MoDE-As are molecular degraders that degrade extracellular proteins via ASGPR, comprising three GalNAc ligands, a POI binding element, and a PEG spacer; in vivo and in vitro results demonstrated that MoDE-A molecules facilitated rapid clearance of α-DNP antibodies or cytokine MIF from circulation, and MoDE-A is the first molecule shown to effectively mediate extracellular protein degradation both
“MoDE-As, or molecular degraders that degrade extracellular proteins via the asialoglycoprotein receptor (ASGPR), represent a novel extracellular protein degradation technology initially reported by Professor David A. Spiegel of Yale University. MoDE-As comprise three GalNAc ligands recognized by ASGPR, a protein-of-interest (POI) binding element, and a polyethylene glycol (PEG) spacer fragment”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [545]

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 1,390 · see citing works
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 · see citing works
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 · see citing works
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 651 · see citing works
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 624 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 338 · see citing works
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 · see citing works
Determination of the Upper Size Limit for Uptake and Processing of Ligands by the Asialoglycoprotein Receptor on Hepatocytesin Vitro and in Vivo
Rensen, P. C. N., Sliedregt, L. A. J. M., Ferns, M., Kieviet, E., van Rossenberg, S. M. W., van Leeuwen, S. H., van Berkel, T. J. C., & Biessen, E. A. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101786200 · Cited by 231 · see citing works
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 228 · see citing works
siRNA Conjugates Carrying Sequentially Assembled Trivalent N-Acetylgalactosamine Linked Through Nucleosides Elicit Robust Gene Silencing In Vivo in Hepatocytes
Matsuda, S., Keiser, K., Nair, J. K., Charissé, K., Manoharan, R. M., Kretschmer, P., Peng, C. G., Kel’in, A. V., Pachamuthu, K., Willoughby, J. L. S., et al. (2015) · ACS Chemical Biology · doi:10.1021/cb501028c · Cited by 222 · see citing works
Temperature dependence of endocytosis mediated by the asialoglycoprotein receptor in isolated rat hepatocytes. Evidence for two potentially rate-limiting steps.
Weigel, P. H., & Oka, J. A. (1981) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)69656-0 · Cited by 198 · see citing works
Recycling of the asialoglycoprotein receptor and the effect of lysosomotropic amines in hepatoma cells.
Schwartz, A. L., Bolognesi, A., & Fridovich, S. E. (1984) · The Journal of Cell Biology · doi:10.1083/jcb.98.2.732 · Cited by 187 · see citing works
Generation of hybridomas secreting murine reaginic antibodies of anti-DNP specificity.
Eshhar, Z., Ofarim, M., & Waks, T. (1980) · The Journal of Immunology · doi:10.4049/jimmunol.124.2.775 · Cited by 176 · see citing works
Fate of receptor and ligand during endocytosis of asialoglycoproteins by isolated hepatocytes.
Bridges, K. R., Harford, J. B., Ashwell, G., & Klausner, R. D. (1982) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.79.2.350 · Cited by 175 · see citing works
Macrophage migration inhibitory factor (MIF) as a therapeutic target for rheumatoid arthritis and systemic lupus erythematosus
Bilsborrow, J. B., Doherty, E. H., Tilstam, P. V., & Bucala, R. (2019) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2019.1656718 · Cited by 169 · see citing works
Hepatocyte entry leads to degradation of autoreactive CD8 T cells
Benseler, V., Warren, A., Vo, M., Holz, L. E., Tay, S. S., Le Couteur, D. G., Breen, E., Allison, A. C., van Rooijen, N., McGuffog, C., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1112251108 · Cited by 164 · see citing works
Asialoglycoprotein receptor 1 mediates productive uptake of N-acetylgalactosamine-conjugated and unconjugated phosphorothioate antisense oligonucleotides into liver hepatocytes
Tanowitz, M., Hettrick, L. A., Revenko, A. S., Kinberger, G. A., Prakash, T. P., & Seth, P. P. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx960 · Cited by 161 · see citing works
Glycoprotein catabolism in rat liver. Lysosomal digestion of iodinated asialo-fetuin
LaBadie, J. H., Chapman, K. P., & Aronson, N. N. (1975) · Biochemical Journal · doi:10.1042/bj1520271 · Cited by 144 · see citing works
The Ashwell–Morell Receptor
Grewal, P. K. (2010) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(10)79013-3 · Cited by 136 · see citing works
The Asialoglycoprotein Receptor Regulates Levels of Plasma Glycoproteins Terminating with Sialic Acid α2,6-Galactose
Steirer, L. M., Park, E. I., Townsend, R. R., & Baenziger, J. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m808689200 · Cited by 125 · see citing works
Fetuin ‐ an old friend revisited
Brown, W. M., Dzięgielewska, K. M., Saunders, N. R., & Møsllgård, K. (1992) · BioEssays · doi:10.1002/bies.950141105 · Cited by 125 · see citing works
Hepatocyte Targeting and Intracellular Copper Chelation by a Thiol-Containing Glycocyclopeptide
Pujol, A. M., Cuillel, M., Renaudet, O., Lebrun, C., Charbonnier, P., Cassio, D., Gateau, C., Dumy, P., Mintz, E., & Delangle, P. (2010) · Journal of the American Chemical Society · doi:10.1021/ja106206z · Cited by 123 · see citing works
Well-Defined Multivalent Ligands for Hepatocytes Targeting via Asialoglycoprotein Receptor
Huang, X., Leroux, J., & Castagner, B. (2016) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.6b00651 · Cited by 120 · see citing works
Expression of Asialoglycoprotein Receptor 1 in Human Hepatocellular Carcinoma
Shi, B., Abrams, M. T., & Sepp‐Lorenzino, L. (2013) · Journal of Histochemistry & Cytochemistry · doi:10.1369/0022155413503662 · Cited by 119 · see citing works
An intrinsic mechanism of secreted protein aging and turnover
Yang, W. H., Aziz, P. V., Heithoff, D. M., Mahan, M. J., Smith, J. W., & Marth, J. D. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1515464112 · Cited by 110 · see citing works
Selectivity of commonly used inhibitors of clathrin-mediated and caveolae-dependent endocytosis of G protein–coupled receptors
Guo, S., Zhang, X., Zheng, M., Zhang, X., Min, C., Wang, Z., Cheon, S. H., Oak, M., Nah, S.-Y., & Kim, K. (2015) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2015.05.024 · Cited by 109 · see citing works
Glycomimetic Ligands for the Human Asialoglycoprotein Receptor
Mamidyala, S. K., Dutta, S., Chrunyk, B. A., Préville, C., Wang, H., Withka, J. M., McColl, A. S., Subashi, T. A., Hawrylik, S. J., Griffor, M. C., et al. (2012) · Journal of the American Chemical Society · doi:10.1021/ja2104679 · Cited by 105 · see citing works
Activation of the Signal Transducer and Activator of Transcription Signaling Pathway in Renal Proximal Tubular Cells by Albumin
Nakajima, H., Takenaka, M., Kaimori, J.-Y., Hamano, T., Iwatani, H., Sugaya, T., Ito, T., Hori, M., & Imai, E. (2004) · Journal of the American Society of Nephrology · doi:10.1097/01.asn.0000109672.83594.02 · Cited by 97 · see citing works
Hyperosmolarity inhibits galactosyl receptor-mediated but not fluid phase endocytosis in isolated rat hepatocytes
Oka, J. A., Christensen, M. D., & Weigel, P. H. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)80168-5 · Cited by 94 · see citing works
Targeted Delivery of DNA Using YEE(GalNAcAH)3, a Synthetic Glycopeptide Ligand for the Asialoglycoprotein Receptor
Merwin, J. R., Noell, G. S., Thomas, W. L., Chiou, H. C., DeRome, M., McKee, T. D., Spitalny, G. L., & Findeis, M. A. (1994) · Bioconjugate Chemistry · doi:10.1021/bc00030a017 · Cited by 93 · see citing works
Clathrin-mediated Endocytosis and Lysosomal Cleavage of Hepatitis B Virus Capsid-like Core Particles
Cooper, A., & Shaul, Y. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601418200 · Cited by 89 · see citing works
Dihydroartemisinin Exerts Its Anticancer Activity through Depleting Cellular Iron via Transferrin Receptor-1
Ba, Q., Zhou, N., Duan, J., Chen, T., Hao, M., Yang, X., Li, J., Yin, J., Chu, R., & Wang, H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042703 · Cited by 84 · see citing works
Therapeutic potential of analogues of amiloride: inhibition of the regulation of intracellular pH as a possible mechanism of tumour selective therapy
Maidorn, R., Cragoe, E. J., & Tannock, I. F. (1993) · British Journal of Cancer · doi:10.1038/bjc.1993.56 · Cited by 82 · see citing works
Design, Synthesis, and Protein Crystallography of Biaryltriazoles as Potent Tautomerase Inhibitors of Macrophage Migration Inhibitory Factor
Dziedzic, P., Cisneros, J. A., Robertson, M. J., Hare, A. A., Danford, N. E., Baxter, R. H. G., & Jorgensen, W. L. (2015) · Journal of the American Chemical Society · doi:10.1021/ja512112j · Cited by 82 · see citing works
Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis
Martínez‐Fábregas, J., Prescott, A. R., van Kasteren, S. I., Pedrioli, D. M. L., McLean, W. H. I., Moles, A., Reinheckel, T., Poli, V., & Watts, C. K. W. (2018) · Nature Communications · doi:10.1038/s41467-018-07741-6 · Cited by 81 · see citing works
The role of sialic acid in determining the life-span of circulating cells and glycoproteins
Bocci, V. A. (1976) · Cellular and Molecular Life Sciences · doi:10.1007/bf01937727 · Cited by 72 · see citing works
Protein Overload Activates Proximal Tubular Cells to Release Vasoactive and Inflammatory Mediators
Zoja, C., Benigni, A., & Remuzzi, G. (1999) · Nephron Experimental Nephrology · doi:10.1159/000020640 · Cited by 69 · see citing works
Distinct effects of endosomal escape and inhibition of endosomal trafficking on gene delivery via electrotransfection
Cervia, L. D., Chang, C., Wang, L., & Yuan, F. (2017) · PLoS ONE · doi:10.1371/journal.pone.0171699 · Cited by 60 · see citing works
Actin Filaments and Microtubules are Involved in Different Membrane Traffic Pathways That Transport Sphingolipids to the Apical Surface of Polarized HepG2 Cells
Zegers, M. M., Zaal, K. J. M., van IJzendoorn, S. C. D., Klappe, K., & Hoekstra, D. (1998) · Molecular Biology of the Cell · doi:10.1091/mbc.9.7.1939 · Cited by 56 · see citing works
Modulation of Mannose and Asialoglycoprotein Receptor Expression Determines Glycoprotein Hormone Half-life at Critical Points in the Reproductive Cycle
Mi, Y., Lin, A., Fiete, D., Steirer, L. M., & Baenziger, J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.544973 · Cited by 53 · see citing works
A Fluorescence Polarization Assay for Binding to Macrophage Migration Inhibitory Factor and Crystal Structures for Complexes of Two Potent Inhibitors
Cisneros, J. A., Robertson, M. J., Valhondo, M., & Jorgensen, W. L. (2016) · Journal of the American Chemical Society · doi:10.1021/jacs.6b04910 · Cited by 43 · see citing works
Inhibition of apolipoprotein E degradation in a post-Golgi compartment by a cysteine protease inhibitor.
Ye, S. Q., Reardon, C. A., & Getz, G. S. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)52902-1 · Cited by 39 · see citing works
NMR study of ligand release from asialoglycoprotein receptor under solution conditions in early endosomes
Onizuka, T., Shimizu, H., Moriwaki, Y., Nakano, T., Kanai, S., Shimada, I., & Takahashi, H. K. (2012) · FEBS Journal · doi:10.1111/j.1742-4658.2012.08643.x · Cited by 39 · see citing works
Hepatocyte cytotoxicity is facilitated by asialoglycoprotein receptor
Guy, C. S., Rankin, S. L., & Michalak, T. I. (2011) · Hepatology · doi:10.1002/hep.24477 · Cited by 35 · see citing works
Structural glycobiology of human α1-acid glycoprotein and its implications for pharmacokinetics and inflammation
Fernandes, C. L., Ligabue‐Braun, R., & Verli, H. (2015) · Glycobiology · doi:10.1093/glycob/cwv041 · Cited by 35 · see citing works
The effect of monensin and chloroquine on the endocytosis and toxicity of chimeric toxins
Ippoliti, R., Ginobbi, P., Lendaro, E., D'Agostino, I., Ombres, D., Benedetti, P. A., Brunori, M., & Citro, G. (1998) · Cellular and Molecular Life Sciences · doi:10.1007/s000180050214 · Cited by 25 · see citing works
A Review of PCSK9 Inhibitors and their Effects on Cardiovascular Diseases
Chen, B., Shi, X., Cui, Y., Hou, A., & Zhao, P. (2019) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026619666190809094203 · Cited by 22 · see citing works
Novel hepatotrophic prodrugs of the antiviral nucleoside 9‐(2‐phosphonylmethoxyethyl)adenine with improved pharmacokinetics and antiviral activity
Biessen, E. A. L., Valentijn, A. R. P. M., de Vrueh, R. L. A., de Bilt, E. V., Sliedregt, L. A. J. M., Prince, P., Bijsterbosch, M. K., BOOM, J. H. V., MAREL, G. A. V. D., Abrahams, P. J., et al. (2000) · The FASEB Journal · doi:10.1096/fj.99-0887com · Cited by 19 · see citing works
Half‐Life Extension through PEGylation
Jevševar, S., & Kunstelj, M. (2012) · doi:10.1002/9783527644827.ch3 · Cited by 6 · see citing works

Flagged first, then by citations

1 of the 53 references couldn’t be matched to a known paper.

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 · see citing works
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 271 · see citing works
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 · see citing works
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 228 · see citing works
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 245 · see citing works
Proximity-Based Modalities for Biology and Medicine
Liu, X., & Ciulli, A. (2023) · ACS Central Science · doi:10.1021/acscentsci.3c00395 · Cited by 204 · see citing works
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 197 · see citing works
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 205 · see citing works
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 190 · see citing works
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 173 · see citing works
Emerging degrader technologies engaging lysosomal pathways
Ding, Y., Xing, D., Fei, Y., & Lu, B. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00624c · Cited by 162 · see citing works
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 141 · see citing works
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 135 · see citing works
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 120 · see citing works
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 106 · see citing works
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 108 · see citing works
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 102 · 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
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 96 · see citing works
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 85 · see citing works
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 85 · see citing works
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 · see citing works
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 80 · see citing works
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 77 · see citing works
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 74 · see citing works
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 73 · see citing works
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 71 · see citing works
Opportunities and challenges of protein-based targeted protein degradation
Shen, F., & Dassama, L. M. K. (2023) · Chemical Science · doi:10.1039/d3sc02361c · Cited by 69 · see citing works
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 66 · see citing works
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 · see citing works
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 66 · see citing works
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 63 · see citing works
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 · see citing works
Biomarker-activated multifunctional lysosome-targeting chimeras mediated selective degradation of extracellular amyloid fibrils
Liu, Z.-Q., Deng, Q.-Q., Qin, G., Yang, J., Zhang, H., Ren, J.-S., & Qu, X.-G. (2023) · Chem · doi:10.1016/j.chempr.2023.06.003 · Cited by 54 · see citing works
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 · see citing works
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 · see citing works
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 58 · see citing works
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 57 · see citing works
Hepatocyte targeting <i>via</i> the asialoglycoprotein receptor
Ramírez-Cortés, F., & Ménová, P. (2025) · RSC Medicinal Chemistry · doi:10.1039/d4md00652f · Cited by 55 · see citing works
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 54 · see citing works
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 51 · see citing works
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 52 · see citing works
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 · see citing works
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 · see citing works
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 47 · see citing works
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 · see citing works
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 46 · see citing works
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 45 · see citing works
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 44 · see citing works
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 · see citing works
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 44 · see citing works
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 42 · see citing works
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 43 · see citing works
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 42 · see citing works
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 42 · see citing works
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 50 · see citing works
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 42 · see citing works
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 41 · see citing works
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 · 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
A plug-and-play monofunctional platform for targeted degradation of extracellular proteins and vesicles
Yao, S., Wang, Y., Tang, Q. J., 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 39 · see citing works
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 · see citing works
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 · see citing works
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 39 · 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
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 37 · see citing works
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 36 · see citing works
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 · see citing works
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 36 · see citing works
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 35 · see citing works
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 32 · see citing works
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 31 · see citing works
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 · see citing works
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 · see citing works
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 29 · see citing works
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 28 · see citing works
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 · see citing works
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 28 · see citing works
Lysosome-targeting chimeras evolve
Paulk, J. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00835-1 · Cited by 28 · see citing works
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 28 · see citing works
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 · see citing works
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 29 · see citing works
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 27 · see citing works
Hijacking Extracellular Targeted Protein Degrader–Drug Conjugates for Enhanced Drug Delivery
Zhao, F.-Z., Wu, Y., Schaefer, K., Zhang, Y., Miao, K., Yao, Z., Ganjave, S. D., Kumru, K., Peters-Clarke, T. M., Inague, A., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c15047 · Cited by 24 · see citing works
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 25 · see citing works
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 · see citing works
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 25 · see citing works
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 25 · see citing works
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 25 · see citing works
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 · see citing works
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 24 · see citing works
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 23 · see citing works
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 23 · see citing works
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 24 · see citing works
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 · see citing works
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 · see citing works
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 21 · 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
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 · see citing works
Targeted protein degradation using the lysosomal pathway
Ghosh, S., Ramadas, B., & Manna, D. (2022) · RSC Medicinal Chemistry · doi:10.1039/d2md00273f · Cited by 21 · see citing works

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 36 · see citing works
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 190 · see citing works
Degradation of extracellular and membrane proteins in targeted therapy: Status quo and quo vadis
Li, Z., Ma, S., Zhang, S., Ma, Z., Du, L., & Li, M. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103716 · Cited by 14 · see citing works
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 · see citing works
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 228 · see citing works

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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks