Introduction

Targeted protein degradation (TPD) has emerged as a promising therapeutic modality, offering a potential solution to address undruggable targets and overcome drug resistance. Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that induce the degradation of target proteins by hijacking the ubiquitin-proteasome system (UPS). This mini-review summarizes recent advancements in PROTAC research over the past five years, focusing on key areas such as PROTAC design and optimization, targeted delivery strategies, and clinical translation.

PROTAC Design and Optimization

Linker Chemistry and Optimization

The linker connecting the target protein-binding ligand and the E3 ligase-binding ligand plays a crucial role in PROTAC activity. Matthias G. J. Baud's group at the University of Strathclyde provided a critical review of current strategies for PROTAC linker design in 2020, highlighting the importance of linker length, flexibility, and chemical composition (Robert I. Troup et al., 2020, Exploration of Targeted Anti-tumor Therapy). Yu Rao's group at Peking University has extensively reviewed the chemistries involved in the synthesis of bifunctional PROTAC degraders, providing valuable insights into linker design and optimization (Chao-Guo Cao et al., 2020, Chemical Society Reviews; Chao-Guo Cao et al., 2021, Chemical Society Reviews; Chao-Guo Cao et al., 2022, Chemical Society Reviews). Jan Kihlberg's group at Uppsala University demonstrated in 2022 that linker-dependent folding significantly impacts PROTAC cell permeability, emphasizing the importance of considering conformational properties in linker design (Vasanthanathan Poongavanam et al., 2022, Journal of Medicinal Chemistry). More recently, Xiaojun Yao's group at China Pharmaceutical University characterized the linker roadmap to govern the rational design of PROTACs (Yawen Dong et al., 2024, Acta Pharmaceutica Sinica B).

E3 Ligase Ligand Discovery and Optimization

The choice of E3 ligase ligand is crucial for PROTAC efficacy and selectivity. Alessio Ciulli's group at the University of Dundee reviewed the discovery and optimization of E3 ligase ligands for PROTAC development in 2020 (Tasuku Ishida et al., 2020, SLAS DISCOVERY). They also demonstrated in 2021 that trivalent PROTACs, which incorporate multiple E3 ligase ligands, can enhance protein degradation through avidity and cooperativity (Satomi Imaide et al., 2021, Nature Chemical Biology). Michael Rapé's and Daniel K. Nomura's groups at UC Berkeley discovered a covalent FEM1B recruiter for targeted protein degradation applications (Nathaniel J. Henning et al., 2022, Journal of the American Chemical Society). H. J. Yang's and Zoran Ranković's groups at Genentech identified phenyl dihydrouracil as an alternative cereblon binder for PROTAC design in 2023 (Jamie Jarusiewicz et al., 2023, ACS Medicinal Chemistry Letters). Miklós Békés's group at Temple University has expanded the E3 ligase repertoire by co-opting KLHDC2 for targeted protein degradation (Christopher M. Hickey et al., 2024, Nature Structural & Molecular Biology).

Addressing Oral Bioavailability and Physicochemical Properties

Achieving oral bioavailability remains a significant challenge for PROTACs due to their large size and complex structure. Keith R. Hornberger's group at Vertex Pharmaceuticals investigated the physicochemical property determinants of oral absorption for PROTAC protein degraders in 2023, providing valuable guidelines for designing orally bioavailable PROTACs (Keith R. Hornberger et al., 2023, Journal of Medicinal Chemistry). Shenxin Zeng's group at Shanghai Institute of Materia Medica reviewed the current advances and development strategies of orally bioavailable PROTACs in 2023 (Shenxin Zeng et al., 2023, European Journal of Medicinal Chemistry). Giulia Caron's and Jan Kihlberg's groups at Uppsala University explored the chemical space of orally bioavailable PROTACs (Giulia Apprato et al., 2024, Drug Discovery Today). Edward Price's group at St. Jude Children's Research Hospital discussed the importance of polarity reducers and chameleonicity in modern drug discovery, including PROTACs (Edward Price et al., 2024, Journal of Medicinal Chemistry).

Targeted Delivery Strategies

Tumor-Specific Activation and Delivery

To enhance PROTAC selectivity and minimize off-target effects, researchers have developed various strategies for tumor-specific activation and delivery. Jian Jin's and Wenyi Wei's groups at the Icahn School of Medicine at Mount Sinai developed folate-caged PROTACs for cancer-selective target degradation (Jing Liu et al., 2020, Journal of the American Chemical Society; Jing Liu et al., 2021, Journal of the American Chemical Society). Guoqiang Dong's and Chunquan Sheng's groups at the University of Science and Technology of China developed aptamer-PROTAC conjugates (APCs) for tumor-specific targeting in breast cancer (Shipeng He et al., 2020, Angewandte Chemie International Edition; Shipeng He et al., 2021, Angewandte Chemie International Edition). Edward W. Tate's group at Imperial College London reported antibody-PROTAC conjugates for HER2-dependent targeted protein degradation of BRD4 (Marı́a Maneiro et al., 2020, ACS Chemical Biology). Huixiong Xu's group at Shanghai Jiao Tong University engineered bioorthogonal POLY-PROTAC nanoparticles for tumor-specific protein degradation and precise cancer therapy (Jing Gao et al., 2022, Nature Communications). Yungen Xu's and Qihua Zhu's groups at the Chinese Academy of Sciences designed nitroreductase (NTR)-responsive PROTACs selectively targeting tumor tissues (Shi Shi et al., 2022, Journal of Medicinal Chemistry). Jinghong Li's group at the National Center for Nanoscience and Technology, China, developed radiotherapy-triggered PROTAC prodrug activation in tumors (Chunrong Yang et al., 2022, Journal of the American Chemical Society). Wei Wang's group at the University of Macau reported bioorthogonal PROTAC prodrugs enabled by on-target activation (Mengyang Chang et al., 2023, Journal of the American Chemical Society). Zhiai Xu's and Haijun Yu's groups at Shanghai Jiao Tong University developed stimuli-activatable PROTACs for precise protein degradation and cancer therapy (Jing Gao et al., 2023, Science Bulletin). Hong-Wei An's, Wanhai Xu's, and Hao Wang's groups at the Chinese Academy of Sciences developed nano PROTACs with anti-hook effect for tumor therapy (Ni-Yuan Zhang et al., 2023, Angewandte Chemie International Edition). Chunquan Sheng's group at the University of Science and Technology of China developed a Drugtamer-PROTAC conjugation strategy for targeted PROTAC delivery and synergistic antitumor therapy (Shipeng He et al., 2024, Advanced Science). Haijun Yu's, Wen Zhang's, and Zhiai Xu's groups at Shanghai Jiao Tong University developed a PROTAC prodrug-integrated nanosensitizer for potentiating radiation therapy of cancer (Shunan Zhang et al., 2024, Advanced Materials). Yang Shi's, Peng Zhang's, and Zhilin Yu's groups at Soochow University developed sulfatase-induced in situ formulation of antineoplastic supra-PROTACs (Ninglin Chen et al., 2024, Journal of the American Chemical Society).

Clinical Translation and Target Validation

Clinical Trials and Target Validation

Several PROTACs have entered clinical trials, demonstrating the potential of this technology for cancer therapy. Craig M. Crews's group at Yale University has published several reviews on the clinical translation of PROTACs (Miklós Békés et al., 2020, Nature Reviews Drug Discovery; Ke Li et al., 2020, Chemical Society Reviews; Deborah Chirnomas et al., 2020, Nature Reviews Clinical Oncology; Miklós Békés et al., 2021, Nature Reviews Drug Discovery; Deborah Chirnomas et al., 2021, Nature Reviews Clinical Oncology; Miklós Békés et al., 2022, Nature Reviews Drug Discovery; Deborah Chirnomas et al., 2022, Nature Reviews Clinical Oncology; Deborah Chirnomas et al., 2023, Nature Reviews Clinical Oncology). Daniel P. Petrylak's group at Yale Cancer Center reported the Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC) (Xīn Gào et al., 2022, Journal of Clinical Oncology). Shaomeng Wang's group at the University of Michigan has been actively involved in the discovery and development of AR PROTAC degraders for prostate cancer (Xin Han et al., 2021, Journal of Medicinal Chemistry; Weiguo Xiang et al., 2021, Journal of Medicinal Chemistry; Xin Han et al., 2023, Journal of Medicinal Chemistry; Weiguo Xiang et al., 2023, Journal of Medicinal Chemistry). I Taylor's group at Arvinas reported that the oral estrogen receptor PROTAC vepdegestrant (ARV-471) is highly efficacious as monotherapy and in combination with CDK4/6 or PI3K/mTOR pathway inhibitors in preclinical ER+ breast cancer models (Sheryl M. Gough et al., 2024, Clinical Cancer Research).

Conclusion

The field of targeted protein degradation has witnessed significant advancements in recent years, with PROTACs emerging as a promising therapeutic modality. Ongoing research efforts are focused on optimizing PROTAC design, developing targeted delivery strategies, and expanding the scope of PROTAC technology to address a wider range of disease targets. The clinical translation of PROTACs is progressing rapidly, with several compounds currently in clinical trials. As the field continues to evolve, PROTACs hold great promise for revolutionizing drug discovery and development.

✨ About This POST
This mini-review post was generated through Scinapse. Scinapse provides reliable research trend analysis using citation analysis and AI technology.
Check out the trends in your field too!
Get started at https://scinapse.io