Modular cytokine receptor-targeting chimeras for targeted degradation of cell surface and extracellular proteins
Open accessAbstract
Targeted degradation of cell surface and extracellular proteins via lysosomal delivery is an important means to modulate extracellular biology. However, these approaches have limitations due to lack of modularity, ease of development, restricted tissue targeting and applicability to both cell surface and extracellular proteins. We describe a lysosomal degradation strategy, termed cytokine receptor-targeting chimeras (KineTACs), that addresses these limitations. KineTACs are fully genetically encoded bispecific antibodies consisting of a cytokine arm, which binds its cognate cytokine receptor, and a target-binding arm for the protein of interest. We show that KineTACs containing the cytokine CXCL12 can use the decoy recycling receptor, CXCR7, to target a variety of target proteins to the lysosome for degradation. Additional KineTACs were designed to harness other CXCR7-targeting cytokines, CXCL11 and vMIPII, and the interleukin-2 (IL-2) receptor-targeting cytokine IL-2. Thus, KineTACs represent a general, modular, selective and simple genetically encoded strategy for inducing lysosomal delivery of extracellular and cell surface targets with broad or tissue-specific distribution.
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.
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?
KineTACs are modular cytokine receptor targeting chimeras for targeted degradation of cell surface and extracellular proteins, based on a fully recombinant bispecific antibody human scaffold; KineTAC CXCL12-Atz targeting PD-L1 effectively degraded PD-L1 in breast cancer cells after 24 h, while single-arm Atz Fab or CXCL12 alone failed to induce PD-L1 degradation, and the platform also degraded HER
“To address the challenge of targeting soluble proteins outside cells, James A. Wells’ team developed cytokine receptor-targeting chimeras (KineTACs), a modular cytokine receptor targeting chimera for the targeted degradation of cell surface and extracellular proteins. KineTAC is a fully recombinant bispecific antibody based on a human scaffold that employs the internalization of homologous”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [546]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A. A., Kim, S., Wilson, C. J., Lehár, J., Kryukov, G. V., Sonkin, D., et al. (2012) · Nature · doi:10.1038/nature11003 · Cited by 7,950 · see citing works
Freeman, G. J., Long, A. J., Iwai, Y., Bourque, K., Chernova, T., Nishimura, H., Fitz, L. J., Malenkovich, N., Okazaki, T., Byrne, M. C., et al. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.7.1027 · Cited by 5,294 · see citing works
Epidermal growth factor receptor mutations in lung cancer
Sharma, S. V., Bell, D. W., Settleman, J., & Haber, D. A. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2088 · Cited by 3,170 · see citing works
Sakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141230798 · Cited by 2,609 · see citing works
Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells
Krönke, J., Udeshi, N. D., Narla, A., Grauman, P., Hurst, S. N., McConkey, M., Svinkina, T., Heckl, D., Comer, E., Li, X., et al. (2014) · Science · doi:10.1126/science.1244851 · Cited by 1,879 · 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
Reprogramming human T cell function and specificity with non-viral genome targeting
Roth, T. L., Puig-Saus, C., Yu, R., Shifrut, E., Carnevale, J., Li, P. J., Hiatt, J., Saco, J., Krystofinski, P., Li, H., et al. (2018) · Nature · doi:10.1038/s41586-018-0326-5 · Cited by 839 · see citing works
Glycosylation as a strategy to improve antibody-based therapeutics
Jefferis, R. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2804 · Cited by 829 · see citing works
PROteolysis TArgeting Chimeras (PROTACs) — Past, present and future
Pettersson, M., & Crews, C. M. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2019.01.002 · Cited by 818 · see citing works
‘Knobs-into-holes’ engineering of antibody C H 3 domains for heavy chain heterodimerization
Ridgway, J. B., Presta, L. G., & Carter, P. M. (1996) · Protein Engineering Design and Selection · doi:10.1093/protein/9.7.617 · Cited by 816 · see citing works
The Intricate Role of CXCR4 in Cancer
Chatterjee, S., Azad, B. B., & Nimmagadda, S. (2014) · Advances in cancer research · doi:10.1016/b978-0-12-411638-2.00002-1 · Cited by 674 · see citing works
LYTACs 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
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
Self-citationA 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
CXCR7 Functions as a Scavenger for CXCL12 and CXCL11
Naumann, U., Cameroni, E., Pruenster, M., Mahabaleshwar, H., Raz, E., Zerwes, H., Rot, A., & Thelen, M. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009175 · Cited by 471 · see citing works
Impact of EGFR expression on colorectal cancer patient prognosis and survival
Spano, J., Lagorce, C., Atlan, D., Milano, G. A., Dômont, J., Benamouzig, R., Attar, A., Bénichou, J., Martin, A., Morère, J., et al. (2004) · Annals of Oncology · doi:10.1093/annonc/mdi006 · Cited by 462 · see citing works
The half-lives of serum immunoglobulins in adult mice
Vieira, P., & Rajewsky, K. (1988) · European Journal of Immunology · doi:10.1002/eji.1830180221 · Cited by 449 · see citing works
Targeted therapeutic options and future perspectives for HER2-positive breast cancer
Wang, J., & Xu, B. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0069-2 · Cited by 396 · see citing works
The unique structural and functional features of CXCL12
Janssens, R., Struyf, S., & Proost, P. (2017) · Cellular and Molecular Immunology · doi:10.1038/cmi.2017.107 · Cited by 380 · see citing works
Igawa, T., Ishii, S., Tachibana, T., Maeda, A., Higuchi, Y., Shimaoka, S., Moriyama, C., Watanabe, T., Takubo, R., Doi, Y., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1691 · Cited by 349 · see citing works
The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target
Goldenberg, D. M., Stein, R., & Sharkey, R. M. (2018) · Oncotarget · doi:10.18632/oncotarget.25615 · Cited by 331 · see citing works
Temporal regulation of EGF signalling networks by the scaffold protein Shc1
Zheng, Y., Zhang, C., Croucher, D. R., Soliman, M. A., St‐Denis, N., Pasculescu, A., Taylor, L., Tate, S. A., Hardy, W. R., Colwill, K., et al. (2013) · Nature · doi:10.1038/nature12308 · Cited by 289 · see citing works
Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab
Lee, H. T., Lee, J., Lim, H., Lee, S. H., Moon, Y. J., Pyo, H. J., Ryu, S. E., Shin, W., & Heo, Y.-S. (2017) · Scientific Reports · doi:10.1038/s41598-017-06002-8 · Cited by 251 · see citing works
Bifunctional small molecules that mediate the degradation of extracellular proteins
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., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00851-1 · Cited by 244 · 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
Hémar, A., Subtil, A., Lieb, M., Morélon, E., Hellio, R., & Dautry‐Varsat, A. (1995) · The Journal of Cell Biology · doi:10.1083/jcb.129.1.55 · Cited by 216 · see citing works
The Latest Battles Between EGFR Monoclonal Antibodies and Resistant Tumor Cells
Cai, W.-Q., Zeng, L.-S., Wang, L., Wang, Y., Cheng, J.-T., Zhang, Y., Han, Z.-W., Zhou, Y., Huang, S.-L., Wang, X.-W., et al. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01249 · Cited by 202 · see citing works
Dovedi, S. J., Elder, M. J., Yang, C., Sitnikova, S. I., Irving, L., Hansen, A., Hair, J., Jones, D. C., Hasani, S., Wang, B., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1445 · Cited by 186 · see citing works
Role of Grb2 in EGF-stimulated EGFR internalization
Yamazaki, T., Zaal, K. J. M., Hailey, D. W., Presley, J. F., Lippincott‐Schwartz, J., & Samelson, L. E. (2002) · Journal of Cell Science · doi:10.1242/jcs.115.9.1791 · Cited by 156 · see citing works
Jang, J., To, C., Clercq, D. J. H. D., Park, E., Ponthier, C. M., Shin, B. H., Mushajiang, M., Nowak, R. P., Fischer, E. S., Eck, M. J., et al. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202003500 · Cited by 151 · see citing works
First targeted protein degrader hits the clinic
Mullard, A. (2019) · Nature Reviews Drug Discovery · doi:10.1038/d41573-019-00043-6 · Cited by 146 · see citing works
Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1
Hsu, E.-C., Rice, M. A., Bermudez, A., Marques, F. J. G., Aslan, M., Liu, S., Ghoochani, A., Zhang, C. A., Chen, Y.-S., Zlitni, A., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1905384117 · Cited by 146 · see citing works
Epidermal Growth Factor Receptor Family and its Role in Gastric Cancer
Arienti, C., Pignatta, S., & Tesei, A. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01308 · Cited by 145 · see citing works
Distinct PD-L1 binding characteristics of therapeutic monoclonal antibody durvalumab
Tan, S., Liu, K., Chai, Y., Zhang, C. W.-H., Gao, S., Gao, G. F., & Qi, J. (2017) · Protein & Cell · doi:10.1007/s13238-017-0412-8 · Cited by 137 · see citing works
Soluble ligands as drug targets
Attwood, M. M., Jonsson, J., Rask‐Andersen, M., & Schiöth, H. B. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0078-4 · Cited by 110 · see citing works
Igawa, T., Haraya, K., & Hattori, K. (2016) · Immunological Reviews · doi:10.1111/imr.12392 · Cited by 99 · see citing works
Lee, G. T., Nagaya, N., Desantis, J., Madura, K., Sabaawy, H. E., Kim, W.-J., Vaz, R. J., Cruciani, G., & Kim, I. Y. (2020) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0417 · Cited by 96 · see citing works
Martinko, A. J., Truillet, C., Julien, O., Diaz, J. E., Horlbeck, M. A., Whiteley, G., Blonder, J., Weissman, J. S., Bandyopadhyay, S., Evans, M. J., et al. (2018) · eLife · doi:10.7554/elife.31098 · Cited by 91 · see citing works
Self-citationFuentes, G., Scaltriti, M., Baselga, J. M., & Verma, C. S. (2011) · Breast Cancer Research · doi:10.1186/bcr2888 · Cited by 74 · see citing works
ERBB2 phosphorylation and trastuzumab sensitivity of breast cancer cell lines
Ginestier, C., Adélaı̈de, J., Gonçalvès, A., Repellini, L., Sircoulomb, F., Letessier, A., Finetti, P., Geneix, J., Charafe‐Jauffret, E., Bertucci, F., et al. (2007) · Oncogene · doi:10.1038/sj.onc.1210528 · Cited by 69 · see citing works
Assessing IRAK4 Functions in ABC DLBCL by IRAK4 Kinase Inhibition and Protein Degradation
Zhang, J., Fu, L., Shen, B., Liu, Y., Wang, W., Cai, X., Kong, L., Yan, Y., Meng, R., Zhang, Z., et al. (2020) · Cell Chemical Biology · doi:10.1016/j.chembiol.2020.08.010 · Cited by 63 · see citing works
Liu, Z., Sun, L., Cai, Y., Shen, S., Zhang, T., Wang, N., Wu, G., Ma, W., Li, S., Suo, C., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-2876 · Cited by 63 · see citing works
Leung, K., Nguyen, A. N., Shi, T., Tang, L., Ni, X., Escoubet, L., MacBeth, K. J., DiMartino, J. F., & Wells, J. A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1813666116 · Cited by 56 · see citing works
Self-citationDual Targeting of the Chemokine Receptors CXCR4 and ACKR3 with Novel Engineered Chemokines
Hanes, M. S., Salanga, C. L., Chowdry, A. B., Comerford, I., McColl, S. R., Kufareva, I., & Handel, T. M. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.675108 · Cited by 47 · see citing works
Stephens, B. S., Ngo, T., Kufareva, I., & Handel, T. M. (2020) · Science Signaling · doi:10.1126/scisignal.aay5024 · Cited by 44 · see citing works
Jin, H., D’Urso, V., Neuteboom, B., McKenna, S. D., Schweickhardt, R. L., Gross, A. W., Fomekong‐Nanfack, Y., Paoletti, A., Carter, C., Toleikis, L., et al. (2021) · OncoImmunology · doi:10.1080/2162402x.2021.1958590 · Cited by 40 · see citing works
Insights into HER2 signaling from step-by-step optimization of anti-HER2 antibodies
Fu, W., Wang, Y., Zhang, Y., Xiong, L., Takeda, H., Ding, L., Xu, Q., He, L., Tan, W., Bethune, A. N., et al. (2014) · mAbs · doi:10.4161/mabs.28786 · Cited by 39 · see citing works
Lim, S.-O. A., Gramespacher, J. A., Pance, K., Rettko, N. J., Solomon, P. E., Jin, J., Lui, I., Elledge, S. K., Liu, J., Bracken, C. J., et al. (2021) · mAbs · doi:10.1080/19420862.2021.1893426 · Cited by 33 · see citing works
Self-citationFu, L., Zhang, J., Shen, B., Kong, L., Liu, Y., Tu, W., Wang, W., Cai, X., Wang, X., Cheng, N., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00103 · Cited by 29 · see citing works
Costantini, S., Raucci, R., Vero, T. D., Castello, G., & Colonna, G. (2013) · Cytokine · doi:10.1016/j.cyto.2013.05.024 · Cited by 27 · see citing works
Joshi, K. K., Phung, W., Han, G., Yin, Y., Kim, I., Sandoval, W. N., & Carter, P. J. (2019) · mAbs · doi:10.1080/19420862.2019.1640549 · Cited by 27 · see citing works
Ovacik, A. M., Li, J., Lemper, M., Danilenko, D. M., Stagg, N. J., Mathieu, M. A., Ellerman, D. A., Gupta, V., Kalia, N., Nguy, T., et al. (2018) · mAbs · doi:10.1080/19420862.2018.1551676 · Cited by 16 · see citing works
Liu, H., Bi, X., Zhou, Y., Shi, R., Yao, S., Qi, J., Feng, H., Feng, M., Yan, J., & Tan, S. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00254-z · Cited by 15 · see citing works
Ma, L., Tong, Y., Zhou, Q., Yang, Z., Yan, H., Chen, Y., Ruo, X., Pan, J., Gou, X., Qian, W., et al. (2021) · Cancer Research · doi:10.1158/1538-7445.am2021-1265 · Cited by 6 · see citing works
Saad, E. B., Oroya, A., & Rudd, C. E. (2020) · Cancer Research · doi:10.1158/1538-7445.am2020-6528 · Cited by 4 · see citing works
Flagged first, then by citations
2 of the 57 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
The present and future of bispecific antibodies for cancer therapy
Klein, C., Brinkmann, U., Reichert, J. M., & Kontermann, R. E. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-00896-6 · Cited by 516 · see citing works
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
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
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
Self-citationThe Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics
Qian, L., Lin, X., Gao, X., Khan, R. U., Liao, J., Du, S., Ge, J., Zeng, S., & Yao, S. Q. (2023) · Chemical Reviews · doi:10.1021/acs.chemrev.2c00915 · Cited by 156 · see citing works
Designed endocytosis-inducing proteins degrade targets and amplify signals
Huang, B., Abedi, M. H., Ahn, G., Coventry, B., Sappington, I., Tang, C., Wang, R., Schlichthaerle, T., Zhang, J. Z., Wang, Y., et al. (2024) · Nature · doi:10.1038/s41586-024-07948-2 · Cited by 167 · see citing works
Strategies to therapeutically modulate cytokine action
Leonard, W. J., & Lin, J. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00746-x · Cited by 121 · 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
A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy
Xiao, Y., He, Z., Li, W., Chen, D., Niu, X., Yang, X., Zeng, W., Wang, M., Qian, Y., Su, Y., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56648-6 · Cited by 98 · see citing works
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
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
Su, L., Tian, Y., Zheng, Q., Cao, Y., Yao, M., Wang, S., Xu, W., Xi, C., Clocchiatti, A., Nie, G., et al. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.01.002 · Cited by 78 · 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
Duan, Q., Jia, H., Chen, W., Qin, C., Zhang, K., Jia, F., Fu, T., Wei, Y., Fan, M., Wu, Q., et al. (2024) · Advanced Science · doi:10.1002/advs.202308924 · Cited by 71 · see citing works
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
Chen, S., Cui, J., Chen, H., Yu, B., & Long, S. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115911 · Cited by 70 · 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 posttranslational modifications by chemically induced proximity for cancer therapy
Peng, Y., Liu, J., Inuzuka, H., & Wei, W. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104572 · Cited by 66 · see citing works
Tian, Y., Miao, Y., Guo, P., Wang, J., & Han, D. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202316089 · Cited by 64 · see citing works
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
Siepe, D. H., Picton, L. K., & García, K. C. (2023) · ACS Synthetic Biology · doi:10.1021/acssynbio.2c00587 · Cited by 61 · see citing works
Targeted degradation of membrane and extracellular proteins with LYTACs
Li, Y., Yang, Y., Zhang, R., Ge, R., & Xie, S. (2024) · Acta Pharmacologica Sinica · doi:10.1038/s41401-024-01364-y · Cited by 61 · see citing works
Journey of PROTAC: From Bench to Clinical Trial and Beyond
Berkley, K., Zalejski, J., Sharma, N., & Sharma, A. K. (2025) · Biochemistry · doi:10.1021/acs.biochem.4c00577 · Cited by 62 · see citing works
Development of Integrin-Facilitated Bispecific Aptamer Chimeras for Membrane Protein Degradation
Sun, W., Zhang, H., Xie, W., Ma, L., Dang, Y., Liu, Y., Li, L., Qu, F., & Tan, W. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.4c04794 · Cited by 60 · 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
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
Chen, Y., Liu, F., Pal, S., & Hu, Q. (2024) · Chemical Society Reviews · doi:10.1039/d4cs00411f · Cited by 55 · see citing works
Moon, B., Kim, Y., & Kim, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241613004 · Cited by 53 · see citing works
Biospecific Chemistry for Covalent Linking of Biomacromolecules
Cao, L., & Wang, L. (2024) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00066 · Cited by 52 · see citing works
Leveraging aptamers for targeted protein degradation
Yang, Z., Pang, Q., Zhou, J., Xuan, C., & Xie, S. (2023) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2023.05.008 · Cited by 50 · see citing works
Shao, J., Lin, X., Wang, H., Zhao, C., Yao, S. Q., Ge, J., Zeng, S., & Qian, L. (2024) · Angewandte Chemie International Edition · doi:10.1002/anie.202319232 · Cited by 50 · 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
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
ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation
Sun, R., Meng, Z., Lee, H.-Y., Offringa, R., & Niehrs, C. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.05.010 · Cited by 43 · 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
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: 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
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
Deubiquitinase-Targeting Chimeras (DUBTACs) as a Potential Paradigm-Shifting Drug Discovery Approach
Ma, Z., Zhou, M., Chen, H., Shen, Q., & Zhou, J. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02975 · Cited by 37 · see citing works
USP28-Based Deubiquitinase-Targeting Chimeras for Cancer Treatment
Wang, Z., Qian, C., Xiong, Y., Zhang, D., Inuzuka, H., Zhong, Y., Xie, L., Chen, X., Jin, J. J., & Wei, W. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c01889 · Cited by 34 · see citing works
USP7-Based Deubiquitinase-Targeting Chimeras Stabilize AMPK
Liu, J., Hu, X., Luo, K., Xiong, Y., Chen, L., Wang, Z., Inuzuka, H., Qian, C., Yu, X., Xie, L., et al. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.4c02373 · Cited by 37 · see citing works
CYpHER: catalytic extracellular targeted protein degradation with high potency and durable effect
Crook, Z. R., Sevilla, G. P., Young, P., Girard, E. J., Phi, T.-D., Howard, M. L., Price, J., Olson, J. M., & Nairn, N. W. (2024) · Nature Communications · doi:10.1038/s41467-024-52975-2 · Cited by 37 · see citing works
Malarvannan, M., Unnikrishnan, S., Monohar, S., Ravichandiran, V., & Paul, D. (2024) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2024.107984 · Cited by 33 · see citing works
Targeted Protein Degradation Mediated by Genetically Engineered Lysosome-Targeting Exosomes
Wang, T., Sun, L., Ren, T., Hou, M., Long, Y., Jiang, J., & He, J. (2023) · Nano Letters · doi:10.1021/acs.nanolett.3c03148 · Cited by 31 · 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
Protein-Based Degraders: From Chemical Biology Tools to Neo-Therapeutics
Ou, L., Setegne, M. T., Elliot, J., Shen, F., & Dassama, L. M. K. (2025) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00595 · Cited by 30 · see citing works
Engineering Covalent Aptamer Chimeras for Enhanced Autophagic Degradation of Membrane Proteins
Shi, Y., Yun, Y., Wang, R., Liu, Z., Wu, Z., Xiang, Y., & Zhang, J. (2025) · Angewandte Chemie International Edition · doi:10.1002/anie.202425123 · 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
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
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
Self-citationDiscovery of VH domains that allosterically inhibit ENPP1
Solomon, P. E., Bracken, C. J., Carozza, J. A., Wang, H., Young, E. P., Wellner, A., Liu, C. C., Sweet-Cordero, A., Li, L., & Wells, J. A. (2023) · Nature Chemical Biology · doi:10.1038/s41589-023-01368-5 · Cited by 27 · see citing works
Self-citationIGF2 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
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
Conditionally Activatable Chimeras for Tumor-Specific Membrane Protein Degradation
Liu, H., Fu, Z., Han, Y., Fang, Y., Shen, W., Chen, Z., Zhu, R., Zhang, H., & Chen, P. R. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.4c06160 · Cited by 26 · see citing works
Guo, C., Gao, F., Wu, G., Li, J., Sheng, C., He, S., & Hu, H. (2024) · Advanced Science · doi:10.1002/advs.202410778 · Cited by 25 · see citing works
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
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
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
Therapeutic potential of cis-targeting bispecific antibodies
Oslund, R., Holland, P. M., Lesley, S. A., & Fadeyi, O. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.07.004 · Cited by 22 · see citing works
Zhou, Y., Liao, Y., Zhao, Y., & Tang, W. (2024) · ChemMedChem · doi:10.1002/cmdc.202300643 · Cited by 22 · see citing works
He, S., Huang, W., Zhu, Y., Gao, F., Fang, Y., Zhu, J., Bao, Y., Dong, G., & Sheng, C. (2025) · Angewandte Chemie International Edition · doi:10.1002/anie.202511467 · Cited by 22 · see citing works
Lesiak, L., Dadina, N., Zheng, S., Schelvis, M., & Schepartz, A. (2023) · ACS Central Science · doi:10.1021/acscentsci.3c01173 · Cited by 22 · see citing works
Yu, S., Shi, T., Li, C., Xie, C., Wang, F., & Liu, X. (2024) · Nano Letters · doi:10.1021/acs.nanolett.4c03102 · 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
Engineered Virus‐Like Nanoparticles Enable Multimodal Protein Degradation for Enhanced Tumor Therapy
Dou, Q., Wang, J., Mao, M., Shui, L., Hu, Y., & Zhang, Y. (2025) · Advanced Materials · doi:10.1002/adma.202507608 · Cited by 21 · see citing works
He, H., Zhou, C., & Chen, X. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c08843 · Cited by 20 · see citing works
Fang, T., Zheng, Z., Li, N., Zhang, Y., Ma, J., Yun, C., & Cai, X. (2024) · Chemical Science · doi:10.1039/d4sc05093b · Cited by 19 · see citing works
Wang, X., Shuai, W., Yang, P., Liu, Y., Zhang, Y., & Wang, G. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102584 · Cited by 19 · see citing works
The application of targeted protein degradation technologies to G protein‐coupled receptors
Keen, A. C., Jörg, M., & Halls, M. L. (2023) · British Journal of Pharmacology · doi:10.1111/bph.16079 · Cited by 19 · see citing works
Generative design of therapeutics that bind and modulate protein states
Chen, T., Hong, L., Yudistyra, V., Vincoff, S., & Chatterjee, P. (2023) · Current Opinion in Biomedical Engineering · doi:10.1016/j.cobme.2023.100496 · Cited by 17 · see citing works
Harnessing the Deubiquitinase USP1 for Targeted Protein Stabilization
Qian, C., Wang, Z., Xiong, Y., Zhang, D., Zhong, Y., Inuzuka, H., Qi, Y., Xie, L., Chen, X., Wei, W., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c01662 · Cited by 20 · see citing works
Dual membrane receptor degradation via folate receptor targeting chimera
Wang, Z., Li, Z., Hogstrom, J. M., Inuzuka, H., Jing, R., Yan, P., Hou, T., Qi, Y., Huang, D., Wang, J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-63882-5 · Cited by 18 · see citing works
Lysosome-targeting chimeras enable targeted protein degradation
Li, B., Li, Y., Zhang, J. J., Badama, S., Zhao, X., Wang, L., Zhang, T. W., Wang, X., Yi, X., Ding, G., et al. (2026) · Cell chemical biology · doi:10.1016/j.chembiol.2026.01.008 · Cited by 18 · see citing works
Design principles and therapeutic applications of novel synthetic WNT signaling agonists
Post, Y., Lu, C., Fletcher, R. B., Yeh, W., Nguyen, H., Lee, S., & Li, Y. (2024) · iScience · doi:10.1016/j.isci.2024.109938 · Cited by 16 · see citing works
Du, J., Han, S., Zhou, H., Wang, J., Wang, F., Zhao, M., Song, R., Li, K., Zhu, H., Zhang, W., et al. (2024) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-024-06804-9 · Cited by 16 · see citing works
Jiang, S., Lv, X., Ouyang, Z., Chi, H., Zeng, Y., Wang, Y., He, J., Chen, J., Chen, J., An, K., et al. (2024) · Angewandte Chemie International Edition · doi:10.1002/anie.202407986 · Cited by 16 · see citing works
Zhou, H., Hou, B., Shan, Y., Huang, L., Chen, F., Ren, S., Zhang, S., Pan, J., Dang, Y., Yu, H., et al. (2025) · Angewandte Chemie International Edition · doi:10.1002/anie.202504233 · Cited by 16 · see citing works
Targeted Extracellular Protein Degradation by Dendronized DNA Chimeras
Zhu, C., Wang, W., Wang, Y., Zhang, W., Zhang, Y., & Li, J. (2024) · ACS Chemical Biology · doi:10.1021/acschembio.3c00645 · Cited by 16 · see citing works
Yun, C., Li, N., Zhang, Y., Fang, T., Ma, J., Zheng, Z., Zhou, S. H., & Cai, X. (2024) · ACS Chemical Biology · doi:10.1021/acschembio.4c00584 · Cited by 15 · see citing works
Ning, Y., Li, B., Wu, C., Feng, L., Huang, X., & Liu, B. (2025) · ACS Nano · doi:10.1021/acsnano.5c00745 · Cited by 15 · see citing works
Chang, X., Qiu, X., Tong, X., Gan, S., Yi, W., Xie, S., Liu, X., Zuo, C., & Tan, W. (2025) · Advanced Science · doi:10.1002/advs.202501222 · Cited by 15 · see citing works
Lu, R. H.-H., Krishna, J., Alp, Y., & Thayumanavan, S. (2026) · Journal of the American Chemical Society · doi:10.1021/jacs.5c17519 · Cited by 15 · see citing works
Functionalized Protein Binders in Developmental Biology
Schnider, S. T., Viganò, M., Affolter, M., & Aguilar, G. (2024) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-112122-025214 · Cited by 13 · see citing works
Mukai, K., Cost, R., Zhang, X. S., Condiff, E., Cotton, J., Liu, X., Boudanova, E., Niebel, B., Piepenhagen, P. A., Cai, X., et al. (2024) · mAbs · doi:10.1080/19420862.2024.2415333 · Cited by 14 · see citing works
Wang, Z., Zheng, M., Li, M., Lu, H., Liu, N., Chen, Y., Yang, N., Zeng, W., Dong, Y., Li, J., et al. (2024) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-24-0319 · Cited by 14 · see citing works
Emerging Concepts of Targeted Protein Degrader Technologies via Lysosomal Pathways
Alam, M. M., Wasim, S., & Lee, S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26125582 · Cited by 14 · see citing works
Nalawansha, D. A., Mazis, G., Husemoen, G., Ashton, K. S., Deng, W., Wurz, R. P., Tran, A. T., Lanman, B. A., Xie, J., Guenette, R. G., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-63128-4 · Cited by 14 · see citing works
Targeted protein degradation technologies: Emerging mechanisms and nano-based innovations
Hou, M., Zhao, R., Wang, S., Jiang, B., & Yan, X. (2025) · Nano Research · doi:10.26599/nr.2025.94907983 · Cited by 14 · see citing works
Recent advances in targeting protein degradation for tumor immunotherapy
Li, S., Jin, Y., Wu, H., Yuan, H., & Zhao, J. (2025) · Journal of Hematology & Oncology · doi:10.1186/s13045-025-01765-4 · Cited by 14 · 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
- Authors
- Pance, K., Gramespacher, J. A., Byrnes, J. R., Salangsang, F., Serrano, J.-A. C., Cotton, A. D., Steri, V., & Wells, J. A.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Wells, James A.
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2022-09-22
- Volume
- 41
- Issue
- 2
- Pages
- 273-281
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC9931583
- OpenAlex
- W4296691508
- Cited by
- 265
- References
- 57
- Citations by year
- 2026: 68 · 2025: 97 · 2024: 58 · 2023: 41 · 2022: 1
- FWCI
- 16.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Biotechnology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (1F31CA265080-01, 5F32CA239417, R01CA248323)
- U.S. Department of Health & Human Services | National Institutes of Health (R35GM122451)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- targeted protein degradation, lysosomal degradation, bispecific antibodies, CXCL12, CXCR7, decoy receptor, CXCL11, interleukin-2 receptor, interleukin-2, cell surface proteins, extracellular proteins, tissue-specific targeting
- MeSH terms
- Proteolysis Targeting Chimera, Cell Membrane, Interleukin-2, Signal Transduction, Receptors, Cytokine, Chemokine CXCL12, Proteolysis
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
