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Cited by 326Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

Targeted protein degradation: advances in drug discovery and clinical practice

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Zhong, Guangcai, Chang, Xiaoyu, Xie, Weilin, Zhou, Xiangxiang·2024·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-024-02004-xPMC PMC11539257
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Abstract

Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing a stark contrast to traditional therapeutic approaches like small molecule inhibitors that primarily focus on inhibiting protein function. This advanced technology capitalizes on the cell’s intrinsic proteolytic systems, including the proteasome and lysosomal pathways, to selectively eliminate disease-causing proteins. TPD not only enhances the efficacy of treatments but also expands the scope of protein degradation applications. Despite its considerable potential, TPD faces challenges related to the properties of the drugs and their rational design. This review thoroughly explores the mechanisms and clinical advancements of TPD, from its initial conceptualization to practical implementation, with a particular focus on proteolysis-targeting chimeras and molecular glues. In addition, the review delves into emerging technologies and methodologies aimed at addressing these challenges and enhancing therapeutic efficacy. We also discuss the significant clinical trials and highlight the promising therapeutic outcomes associated with TPD drugs, illustrating their potential to transform the treatment landscape. Furthermore, the review considers the benefits of combining TPD with other therapies to enhance overall treatment effectiveness and overcome drug resistance. The future directions of TPD applications are also explored, presenting an optimistic perspective on further innovations. By offering a comprehensive overview of the current innovations and the challenges faced, this review assesses the transformative potential of TPD in revolutionizing drug development and disease management, setting the stage for a new era in medical therapy.

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  • PROTACs are categorized into distinct generations; first-generation employed peptide-based ligands, second-generation introduced small molecule ligands with improved drug-like properties, and within the second generation rational design enabled multiple candidates to advance into clinical development.

    “First-generation PROtAcs employed peptide-based ligands, while second-generation PROtAcs introduced small molecule ligands with improved drug-like properties; it is within this generation that rational design has enabled multiple candidates to advance into clinical development (Zhong et al. 2024).”

    From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Zhong et al. 2024

    Split into 3 atoms — 1 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • PROTACs targeting PLK1, BTK, BRAF(V600E) and NTRK have exhibited promising pre-clinical and clinical success across a range of cancers.

    “PROtAcs targeting PlK1, BtK, BRAF (v600e) and NtRK have exhibited promising pre-clinical and clinical success across a range of cancers (li et al. 2020;lier et al. 2022;Zhong et al. 2024).”

    From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Zhong et al. 2024

    The sections on BTK and BRAF degraders report promising preclinical activity, and the BTK section reports preliminary clinical efficacy in B-cell malignancies. The NTRK section reports effective TRKC degradation and a degrader entering trials, while the BRAF section says its trial is underway—not that either has achieved clinical success. Searches for PLK1 and polo-like kinase 1 did not locate support for that target in our copy. Page numbers were not provided. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Zhong, G., Chang, X., Xie, W., & Zhou, X.
Affiliations
  • Shandong Provincial Hospital (CN)
  • Zhengzhou University (CN)
  • Shandong First Medical University (CN)
  • Shandong University (CN)
Corresponding author
  • Xie, Weilin
  • Zhou, Xiangxiang
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2024-11-06
Volume
9
Issue
1
Pages
308-308
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-024-02004-x
PMC
PMC11539257
OpenAlex
W4404054585
Cited by
326
References
71
Citations by year
2026: 190 · 2025: 135 · 2024: 1
FWCI
13.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (No. 82170189, No.81800194)
  • Natural Science Foundation of Shandong Province (ZR2021YQ51)
  • Shandong First Medical University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Keywords
targeted protein degradation, PROTACs, molecular glues, proteasome, lysosomal degradation, drug design, clinical trials, combination therapy, drug resistance, drug development
MeSH terms
Humans, Lysosomes, Proteasome Endopeptidase Complex, Drug Discovery, Proteolysis

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