RNA‐PROTACs: Degraders of RNA‐Binding Proteins

Ghidini, Alice; Cléry, Antoine; Halloy, François; Allain, Frédéric H. T.; Hall, Jonathan

doi:10.1002/anie.202012330

Cited by 199Protein Degradation and InhibitorsChemical Synthesis and AnalysisRNA Interference and Gene Delivery

RNA‐PROTACs: Degraders of RNA‐Binding Proteins

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Ghidini, Alice, Cléry, Antoine, Halloy, François, Allain, Frédéric H. T., Hall, Jonathan·2021·Angewandte Chemie International Edition

DOI 10.1002/anie.202012330PMC PMC7898822

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Abstract

Defects in the functions of RNA binding proteins (RBPs) are at the origin of many diseases; however, targeting RBPs with conventional drugs has proven difficult. PROTACs are a new class of drugs that mediate selective degradation of a target protein through a cell's ubiquitination machinery. PROTACs comprise a moiety that binds the selected protein, conjugated to a ligand of an E3 ligase. Herein, we introduce RNA‐PROTACs as a new concept in the targeting of RBPs. These chimeric structures employ small RNA mimics as targeting groups that dock the RNA‐binding site of the RBP, whereupon a conjugated E3‐recruiting peptide derived from the HIF‐1α protein directs the RBP for proteasomal degradation. We performed a proof‐of‐concept demonstration with the degradation of two RBPs—a stem cell factor LIN28 and a splicing factor RBFOX1—and showed their use in cancer cell lines. The RNA‐PROTAC approach opens the way to rapid, selective targeting of RBPs in a rational and general fashion.

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RNA-PROTACs use an RNA consensus sequence as the RBP-binding warhead, linked to an E3 ligase-binding element.
“RNA-PROTACs use an RNA consensus sequence as the RBP-binding warhead, linked to an E3 ligase-binding element220.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [220]
Such constructs have been shown to reduce levels of the RBP LIN28A and the transcription factors ERG and LEF1 in various human cancer cell lines.
“Such constructs have been shown to reduce levels of the RBP LIN28A and the transcription factors ETS transcription factor (ERG) and lymphoid enhancer-binding factor 1 (LEF1) in various human cancer cell lines.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [220]

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Donner, A. J., Bell, T. A., Greenlee, S., Graham, M. J., & Crooke, R. M. (2018) · Nucleic Acid Therapeutics · doi:10.1089/nat.2018.0723 · Cited by 17 · see citing works
Challenges with risk mitigation in academic drug discovery: finding the best solution
Roy, A. (2018) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2019.1553952 · Cited by 12 · see citing works
Arvinas, Pfizer Team Up on PROTACs
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Research and Development of Oligonucleotides Targeting MicroRNAs (miRNAs)
Malinowska, A. L., & Hall, J. (2019) · Royal Society of Chemistry eBooks · doi:10.1039/9781788015714-00151 · Cited by 2 · see citing works
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Sorted by citations

PROTAC targeted protein degraders: the past is prologue
Békés, M., Langley, D. R., & Crews, C. M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00371-6 · Cited by 3,395 · see citing works
Proteolysis-targeting chimeras (PROTACs) in cancer therapy
Li, X., Pu, W., Zheng, Q., Ai, M., Chen, S., & Peng, Y. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01434-3 · Cited by 374 · see citing works
“In future, the design and optimization of these oligonucleotide-based PROTACs, targeting oncogenic RBPs (e.g. IGF2BPs and YBX1) and DBPs (e.g. c-myc and STAT3), should be extensively investigated for targeted cancer therapy.”
BackgroundInfluential
PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)
He, M., Cao, C., Ni, Z., Liu, Y., Song, P., Hao, S., He, Y., Sun, X., & Rao, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00999-9 · Cited by 283 · see citing works
Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders
Diehl, C. J., & Ciulli, A. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00387b · Cited by 259 · see citing works
TF-PROTACs Enable Targeted Degradation of Transcription Factors
Liu, J., Chen, H., Kaniskan, H. Ü., Xie, L., Chen, X., Jin, J., & Wei, W. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c03852 · Cited by 247 · see citing works
Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation
Bond, M. J., & Crews, C. M. (2021) · RSC Chemical Biology · doi:10.1039/d1cb00011j · Cited by 227 · see citing works
RNA-binding proteins and cancer metastasis
Wang, S., Sun, Z., Lei, Z., & Zhang, H. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.03.018 · Cited by 175 · see citing works
Bridged Proteolysis Targeting Chimera (PROTAC) Enables Degradation of Undruggable Targets
Xiong, Y., Zhong, Y., Yim, H., Yang, X., Park, K.-S., Xie, L., Poulikakos, P. I., Han, X., Xiong, Y., Chen, X., et al. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c09255 · Cited by 154 · see citing works
Expanding the arsenal of E3 ubiquitin ligases for proximity-induced protein degradation
Kannt, A., & Đikić, I. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.04.007 · Cited by 148 · see citing works
c-Myc-Targeting PROTAC Based on a TNA-DNA Bivalent Binder for Combination Therapy of Triple-Negative Breast Cancer
Li, X., Zhang, Z., Gao, F., Ma, Y., Wei, D., Lu, Z., Chen, S., Wang, M., Wang, Y., Xu, K., et al. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c02619 · Cited by 145 · see citing works
Destruction of DNA‐Binding Proteins by Programmable Oligonucleotide PROTAC (O'PROTAC): Effective Targeting of LEF1 and ERG
Shao, J., Yan, Y., Ding, D., Wang, D., He, Y., Pan, Y., Yan, W., Kharbanda, A., Li, H., & Huang, H. (2021) · Advanced Science · doi:10.1002/advs.202102555 · Cited by 120 · see citing works
Aptamer-Based Targeted Protein Degradation
Liu, Y., Qian, X., Ran, C., Li, L., Fu, T., Su, D., Xie, S., & Tan, W. (2023) · ACS Nano · doi:10.1021/acsnano.2c10379 · Cited by 106 · see citing works
PROTAC technology: From drug development to probe technology for target deconvolution
Yan, S., Zhang, G., Luo, W., Xu, M., Peng, R., Du, Z., Liu, Y., Bai, Z., Xiao, X., & Qin, S. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116725 · Cited by 92 · see citing works
Sulfatase-Induced In Situ Formulation of Antineoplastic Supra-PROTACs
Chen, N., Zhang, Z., Liu, X., Wang, H., Guo, R.-C., Wang, H., Hu, B., Shi, Y., Zhang, P., Liu, Z., et al. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.4c00826 · Cited by 90 · 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
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
The rise of degrader drugs
Teng, M., & Gray, N. S. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.06.020 · Cited by 67 · see citing works
Recent Advances of Degradation Technologies Based on PROTAC Mechanism
Xiao, M., Zhao, J., Wang, Q., Liu, J., & Ma, L. (2022) · Biomolecules · doi:10.3390/biom12091257 · Cited by 66 · see citing works
“In 2019, RNA-PROTAC was developed to degrade RNA binding proteins (RBPs) [50].”
Background
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
OligoTRAFTACs: A generalizable method for transcription factor degradation
Samarasinghe, K. T. G., An, E., Genuth, M. A., Chu, L., Holley, S. A., & Crews, C. M. (2022) · RSC Chemical Biology · doi:10.1039/d2cb00138a · Cited by 60 · 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 58 · see citing works
“splicing factor) in two cancer cell lines via VHL-mediated pathway [76].”
Background
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
“This concept has led to the development of RNA-PROTACs, a novel class of RBP-targeted chimeric degraders capable of effecting protease-mediated degradation of RBPs. Notably, this approach has successfully enabled the degradation of two distinct RBP targets, namely Lin28 and RBFOX1 62 .”
BackgroundInfluential
G4-PROTAC: targeted degradation of a G-quadruplex binding protein
Patil, K. M., Chin, D., Seah, H. L., Shi, Q., Lim, K. W., & Phan, A. T. (2021) · Chemical Communications · doi:10.1039/d1cc05025g · Cited by 57 · 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
“Ghidini et al.(105) introduced a new concept and developed a bifunctional molecule RNA-PROTAC to achieve the degradation of two RBPs (Fig.”
Background
DNA framework-engineered chimeras platform enables selectively targeted protein degradation
Zhou, L.-M., Yu, B., Gao, M., Chen, R., Li, Z., Gu, Y., Bian, J., & Ma, Y. (2023) · Nature Communications · doi:10.1038/s41467-023-40244-7 · Cited by 57 · see citing works
Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One
Salerno, A., Seghetti, F., Caciolla, J., Uliassi, E., Testi, E., Guardigni, M., Roberti, M., Milelli, A., & Bolognesi, M. L. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00302 · Cited by 55 · see citing works
Innovative developments and emerging technologies in RNA therapeutics
Halloy, F., Biscans, A., Bujold, K. E., Debacker, A. J., Hill, A. C., Lacroix, A., Luige, O., Strömberg, R., Sundström, L., Vogel, J., et al. (2022) · RNA Biology · doi:10.1080/15476286.2022.2027150 · Cited by 54 · see citing works
“The first reported single strand oligonucleotide-based PROTAC, termed RNA-PROTAC, was introduced as a proofof-concept for the degradation of two RBPs, LIN28 and RBFOX1 [228] (Fig.”
BackgroundSelf-citation
Nucleic-Acid-Based Targeted Degradation in Drug Discovery
Wang, W., He, S., Dong, G., & Sheng, C. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00875 · Cited by 55 · see citing works
Antitumor Effect of Anti‐c‐Myc Aptamer‐Based PROTAC for Degradation of the c‐Myc Protein
Wang, Y., Yang, G., Zhang, X., Bai, R., Yuan, D., Gao, D., He, Q., Yuan, Y., Zhang, X., Kou, J., et al. (2024) · Advanced Science · doi:10.1002/advs.202309639 · Cited by 51 · see citing works
Applications of Bacterial Degrons and Degraders — Toward Targeted Protein Degradation in Bacteria
Izert, M. A., Klimecka, M. M., & Górna, M. W. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.669762 · Cited by 47 · see citing works
Novel strategies and promising opportunities for targeted protein degradation: An innovative therapeutic approach to overcome cancer resistance
Zhu, H., Wang, J., Zhang, Q., Pan, X., & Zhang, J. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108371 · Cited by 48 · see citing works
Unlocking the potential of PROTACs: A comprehensive review of protein degradation strategies in disease therapy
Bhole, R. P., Kute, P. R., Chikhale, R. V., Bonde, C. G., Pant, A. M., & Gurav, S. S. (2023) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2023.106720 · Cited by 48 · see citing works
ARE-PROTACs Enable Co-degradation of an Nrf2–MafG Heterodimer
Ji, J., Ma, S., Zhu, Y., Zhao, J., Tong, Y., You, Q., & Jiang, Z. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01909 · Cited by 45 · see citing works
Targeting key proteins involved in transcriptional regulation for cancer therapy: Current strategies and future prospective
Pei, H., Guo, W., Peng, Y., Xiong, H., & Chen, Y. (2022) · Medicinal Research Reviews · doi:10.1002/med.21886 · Cited by 45 · see citing works
hnRNP A1 in RNA metabolism regulation and as a potential therapeutic target
Feng, J., Zhou, J. J., Lin, Y., & Huang, W. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.986409 · Cited by 44 · see citing works
Development of miRNA-based PROTACs targeting Lin28 for breast cancer therapy
Xu, J., Zhao, X., Liang, X., Guo, D., Wang, J., Wang, Q., & Tang, X. (2024) · Science Advances · doi:10.1126/sciadv.adp0334 · Cited by 44 · see citing works
“However, TFs are usually involved in many gene expression, which leads to the unfavorable specificity and affinities of oligonucleotides/TFs and requires high concentration of oligonucleotide-based PROTACs ( 35 , 36 ).”
Beyond canonical PROTAC: biological targeted protein degradation (bioTPD)
Wang, H., Zhou, R., Xu, F., Yang, K., Zheng, L., Zhao, P., Shi, G., Dai, L., Xu, C., Yu, L., et al. (2023) · Biomaterials Research · doi:10.1186/s40824-023-00385-8 · Cited by 46 · see citing works
“Later, Crews’ group [194] further developed the second generation of TRAFTACs technology called oligoTRAFTAC.”
Background
CELF Family Proteins in Cancer: Highlights on the RNA-Binding Protein/Noncoding RNA Regulatory Axis
Aghdam, M. N., Garcia-Garduño, T.-C., & Jave‐Suárez, L. F. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011056 · Cited by 40 · see citing works
“Finally, RNA-PROTACs are a novel type of chimeric oligonucleotide that directly dock into an RBP’s RNA binding site and guide the RBP towards proteasomal destruction through a conjugated E3-recruiting peptide [180].”
Background
Unconventional PROTACs for Targeted Protein Degradation in Cancer Therapy
Zhang, X., Song, Z., Zhang, X., Zou, J., Yu, G., Chen, X. S., & Wang, S. (2025) · Angewandte Chemie International Edition · doi:10.1002/anie.202507702 · Cited by 41 · see citing works
Recent advances in targeted protein degraders as potential therapeutic agents
Yang, N., Kong, B., Zhu, Z., Huang, F., Zhang, L., Lu, T., Chen, Y., Zhang, Y., & Jiang, Y. (2023) · Molecular Diversity · doi:10.1007/s11030-023-10606-w · Cited by 41 · see citing works
“13) targets the Lin28 protein, a stem cell factor, and oncoprotein of high interest as a potential drug target for several diseases [58].”
Nucleotide-amino acid π-stacking interactions initiate photo cross-linking in RNA-protein complexes
Knörlein, A., Sarnowski, C. P., de Vries, T., Stoltz, M., Götze, M., Aebersold, R. H., Allain, F. H. ‐., Leitner, A., & Hall, J. (2022) · Nature Communications · doi:10.1038/s41467-022-30284-w · Cited by 39 · see citing works
Self-citation
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
FAM120A couples SREBP-dependent transcription and splicing of lipogenesis enzymes downstream of mTORC1
Cho, S., Chun, Y., He, L., Ramirez, C. B., Ganesh, K. S., Jeong, K., Song, J., Cheong, J., Li, Z., Choi, J., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.07.017 · Cited by 38 · see citing works
Cooperatively designed aptamer-PROTACs for spatioselective degradation of nucleocytoplasmic shuttling protein for enhanced combinational therapy
Liu, R., Liu, Z., Chen, M., Xing, H., Zhang, P., & Zhang, J. (2023) · Chemical Science · doi:10.1039/d3sc04249a · Cited by 38 · see citing works
Targeted protein degradation at the host–pathogen interface
Grohmann, C., Marapana, D. S., & Ebert, G. (2021) · Molecular Microbiology · doi:10.1111/mmi.14849 · Cited by 37 · see citing works
Oligo-PROTAC strategy for cell-selective and targeted degradation of activated STAT3
Hall, J., Zhang, Z., Bhattacharya, S., Wang, D., Alcantara, M. B., Liang, Y., Swiderski, P. M., Forman, S. J., Kwak, L. W., Vaidehi, N., et al. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102137 · Cited by 38 · see citing works
Self-citation
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
PROTAC Degrader of Estrogen Receptor α Targeting DNA-Binding Domain in Breast Cancer
Zhang, X., Zhang, Z., Xue, X., Fan, T., Tan, C., Liu, F., Tan, Y. C., & Jiang, Y. (2022) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.2c00109 · Cited by 37 · see citing works
Overview of host-directed antiviral targets for future research and drug development
Gu, X., Zheng, M., Gao, Y. M., Lin, S. J., Zhang, X., Chen, C., Zhu, H., Sun, W., & Zhang, Y. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.03.011 · Cited by 32 · see citing works
“Inspired by targeted protein degradation techniques, a novel approach for the targeted degradation of RNA-binding proteins, known as RNA-PROTAC, has been developed 331 .”
Hydrophobic tag tethering degrader as a promising paradigm of protein degradation: Past, present and future perspectives
Ha, S., Zhu, J., Xiang, H., & Luo, G. (2023) · Chinese Chemical Letters · doi:10.1016/j.cclet.2023.109192 · Cited by 34 · see citing works
From PROTAC to TPD: Advances and Opportunities in Targeted Protein Degradation
Wang, S., He, F., Tian, C., & Sun, A. (2024) · Pharmaceuticals · doi:10.3390/ph17010100 · Cited by 32 · see citing works
“Similarly, Hall J designed an RNA-PROTAC based on RNA oligomers and achieved the intracellular degradation of the RNA-binding protein LIN28 by the 26S proteasome, whose warhead is also an intrinsic recognition sequence for LIN28 [61].”
Background
Targeting the “undruggable”: RNA-binding proteins in the spotlight in cancer therapy
Mir, C., Garcia‐Mayea, Y., & LLeonart, M. E. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.06.008 · Cited by 32 · 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 32 · see citing works
“A new type of PROTAC, so-called RNA-PROTAC, aims to degrade RNA binding proteins (RBPs), a class that until now has been proven difficult to target pharmacologically [92].”
BackgroundInfluential
Telomere Targeting Chimera Enables Targeted Destruction of Telomeric Repeat-Binding Factor Proteins
Wang, Z., Liu, J., Chen, H., Qiu, X., Xie, L., Kanıskan, H. Ü., Chen, X., Jin, J. J., & Wei, W. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c02783 · Cited by 32 · see citing works
Discovery of the GSH responsive “Y-PROTACs” targeting ALK and CDK4/6 as a potential treatment for cancer
Wang, S., Luo, D., Pu, C., Ma, X., Zhang, H., Feng, Z., Deng, R., Yu, S., Liu, Y., Huang, Q., et al. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.115082 · Cited by 31 · see citing works
G‐Quadruplex RNA Based PROTAC Enables Targeted Degradation of RNA Binding Protein FMRP for Tumor Immunotherapy
Peng, R., Huang, Q., Wang, L., Qiao, G., Huang, X., Jiang, J., & Chu, X. (2024) · Angewandte Chemie International Edition · doi:10.1002/anie.202402715 · 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
Therapeutic targeting of RNA-binding protein by RNA-PROTAC
Li, X., Pu, W., Chen, S., & Peng, Y. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.04.032 · Cited by 30 · see citing works
Targeting RNA ‐binding proteins with small molecules: Perspectives, pitfalls and bifunctional molecules
Li, Q., & Kang, C. (2023) · FEBS Letters · doi:10.1002/1873-3468.14710 · Cited by 28 · see citing works
RNATACs: Multispecific small molecules targeting RNA by induced proximity
Song, Y., Cui, J., Zhu, J., Kim, B., Kuo, M.-L., & Potts, P. R. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.05.006 · Cited by 28 · see citing works
Progress of proteolysis-targeting chimeras (PROTACs) delivery system in tumor treatment
Fan, L., Tong, W., Wei, A., & Mu, X. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.133680 · 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
PROTAC-Based Protein Degradation as a Promising Strategy for Targeted Therapy in Sarcomas
Mancarella, C., Morrione, A., & Scotlandi, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242216346 · Cited by 28 · see citing works
“In parallel, mutations of Cullin 2 ( CUL2 ) determined the resistance to PROTACs recruiting VHL E3 ligase [91,94].”
Background
The new direction of drug development: Degradation of undruggable targets through targeting chimera technology
Liang, X., Ren, H., Han, F., Liang, R., Zhao, J., & Liu, H. S. (2023) · Medicinal Research Reviews · doi:10.1002/med.21992 · Cited by 28 · see citing works
Novel roles of RNA-binding proteins in drug resistance of breast cancer: from molecular biology to targeting therapeutics
Cen, Y., Chen, L., Liu, Z., Lin, Q., Fang, X., Yao, H., & Gong, C. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01352-x · Cited by 27 · see citing works
“As RNA-PROTACs are inherently unstable in the presence of nucleases and/or proteases, nanoscale drug delivery systems might be introduced to protect RNA-PROTACs from decay, thereby increasing their biological efficiency in vivo [117].”
BackgroundInfluential
The aptamer-based RNA-PROTAC
Xu, Y., Yuan, Y., Fu, D., Fu, Y., Zhou, S., Yang, W., Wang, X., Li, G., Dong, J., Du, F., et al. (2023) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2023.117299 · Cited by 27 · see citing works
Integrating Proteolysis‐Targeting Chimeras (PROTACs) with Delivery Systems for More Efficient and Precise Targeted Protein Degradation
Lin, J., Chen, Z., Zhang, D., Zhang, N., Chen, H., & Guo, D. (2025) · Macromolecular Rapid Communications · doi:10.1002/marc.202401051 · Cited by 26 · see citing works
Fates and functions of RNA ‐binding proteins under stress
Goswami, B., Nag, S., & Ray, P. S. (2023) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1825 · Cited by 24 · see citing works
“As cellular stress responses are intrinsic to multiple pathological conditions, the central role of RBPs in mediating stress responses makes them attractive targets for developing therapeutic strategies (Bertoldo et al., 2023; Ghidini et al., 2021).”
Background
Advancing Design Strategy of PROTACs for Cancer Therapy
Luo, H., Tian, Y., Abdullah, R., Zhang, B., Ma, Y., & Zhang, G. (2025) · MedComm · doi:10.1002/mco2.70258 · Cited by 22 · see citing works
“In 2020, Ghidini et al. [79] reported the RNA-based-PROTACs for degrading RNA-binding protein (RBP) proteins.”
Targeting oncogenic transcriptional factor c-myc by oligonucleotide PROTAC for the treatment of hepatocellular carcinoma
Ai, M., Ma, H., He, J., Xu, F., Ming, Y., Ye, Z., Zheng, Q., Luo, D., Yang, K., Li, J., et al. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116978 · Cited by 21 · see citing works
Key advances and application prospects of PROTAC technologies in the next 5 years
Qin, S., & Xiao, X. (2025) · Future Medicinal Chemistry · doi:10.1080/17568919.2025.2498875 · Cited by 21 · see citing works
Emerging Strategies in Proteolysis-Targeting Chimeras (PROTACs): Highlights from 2022
Rekha, T. N., & Shin, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065190 · Cited by 20 · see citing works
“Recently, degraders such as transcription factor TF-PROTACs [49] and RNA- PROTACs [50] have also been developed to target undruggable TFs and RNA-binding proteins, respectively, with small-molecule binding sites.”
BackgroundInfluential
Targeting micro-environmental pathways by PROTACs as a therapeutic strategy
Liu, J., Peng, Y., Inuzuka, H., & Wei, W. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.07.001 · Cited by 20 · see citing works
Insights on the biological functions and diverse regulation of RNA-binding protein 39 and their implication in human diseases
Eléouët, M. P., Lu, C., Zhou, Y., Yang, P. X., Ma, J., & Xu, G. (2022) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2022.194902 · Cited by 19 · see citing works
Hydrogen Peroxide‐Inducible PROTACs for Targeted Protein Degradation in Cancer Cells
Yu, D., Fan, H., Zhou, Z., Zhang, Y., Sun, J., Wang, L., Jia, Y., Tian, J., Campbell, A., Mi, W., et al. (2023) · ChemBioChem · doi:10.1002/cbic.202300422 · Cited by 20 · see citing works
Small molecules modulating RNA splicing: a review of targets and future perspectives
Bouton, L., Ecoutin, A., Malard, F., & Campagne, S. (2024) · RSC Medicinal Chemistry · doi:10.1039/d3md00685a · Cited by 19 · see citing works
MicroRNA‐Triggered Programmable DNA‐Encoded Pre‐PROTACs for Cell‐Selective and Controlled Protein Degradation
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A heterobifunctional molecule recruits cereblon to an RNA scaffold and activates its PROTAC function
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“The respective RNA-warheaded PROTAC molecules successfully destroyed not only LIN28 but also RBFOX1 in myelogenous leukemia K562 and embryonic kidney-derived HEK293 cells [24].”
Background
Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety
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“RNA ‐ PROTACs, utilizing short RNA mimics, are being developed to target and degrade RBPs.”
Background
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“Proof-of-concept RNA-PROTACs do not show quantitative degradation, likely due to the absence of structure − activity relationship (SAR) studies aimed at optimizing linker length.”
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Self-citation
Circular mRNA encoded PROTAC (RiboPROTAC) as a new platform for the degradation of intracellular therapeutic targetsPreprint
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Authors: Ghidini, A., Cléry, A., Halloy, F., Allain, F. H. T., & Hall, J.
Affiliations: ETH Zurich (CH)
Corresponding author: Hall, Jonathan
ORCID: Ghidini, Alice
Cléry, Antoine
Halloy, François
Allain, Frédéric H. T.
Hall, Jonathan
Venue: Angewandte Chemie International Edition
Publisher: Wiley
Published: 2020-12-10
Volume: 60
Issue: 6
Pages: 3163-3169
ISSN: 1433-7851 (ISSN-L)
1521-3773
DOI: 10.1002/anie.202012330
PMC: PMC7898822
OpenAlex: W3096947063
Cited by: 197
References: 82
Citations by year: 2026: 28 · 2025: 34 · 2024: 42 · 2023: 40 · 2022: 37 · 2021: 14 · 2020: 1
FWCI: 7.54
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Angewandte Chemie International Edition (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Repository for Publications and Research Data (ETH Zurich) (publishedVersion, cc-by)
Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
ETH Zürich Research Collection (cc-by)
Funders: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (NCCR RNA & Disease)
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: PROTACs, RNA-binding proteins, protein degradation, E3 ubiquitin ligase, Lin28, RBFOX1, proteasomal degradation, cancer therapy
MeSH terms: RNA Splicing Factors, Base Sequence, Binding Sites, Humans, Oligonucleotides, Peptides, RNA, RNA-Binding Proteins, Ubiquitin-Protein Ligases, Cell Line, Tumor, Proteolysis

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RNA‐PROTACs: Degraders of RNA‐Binding Proteins

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