Discovery of selective platelet-derived growth factor receptor-beta (PDGFR-β) bifunctional small-molecule degraders

Si, Ru; Liu, Nanxin; Wang, Jin; Zhang, Qingqing; Li, Yanchen; Pan, Xiaoyan; Zhang, Jie

doi:10.1016/j.bmc.2022.117115

Cited by 8 publications

(5 citation statements)

References 46 publications

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“…This study demonstrates the potential of utilizing bioorthogonal reactions to discover novel PROTACs. It opens a new pathway for developing more efficient and specific antitumor drugs, essential for drug discovery and cancer treatment (Si et al, 2023).…”

Section: Advanced Strategies For Protacsmentioning

confidence: 99%

“…The design of potent, cell‐specific PROTAC molecules with favorable pharmacokinetic and safety profiles remains a critical area of research (Kargbo, 2023; Kou et al, 2023; Mukerjee et al, 2023; Zeng et al, 2023). The quest for optimal PROTACs involves balancing properties like molecular size, solubility, and bioavailability, which are pivotal for their in vivo efficacy and tolerability (Cheng et al, 2023; Liu et al, 2023; Si et al, 2023; Silva et al, 2022; Zeng et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

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Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety

Zhang,

Xie,

Ran

et al. 2024

Journal Cellular Physiology

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Proteolysis Targeting Chimeras (PROTACs) represent a significant advancement in therapeutic drug development by leveraging the ubiquitin‐proteasome system to enable targeted protein degradation, particularly impacting oncology. This review delves into the various types of PROTACs, such as peptide‐based, nucleic acid‐based, and small molecule PROTACs, each addressing distinct challenges in protein degradation. It also discusses innovative strategies like bridged PROTACs and conditional switch‐activated PROTACs, offering precise targeting of previously “undruggable” proteins. The potential of PROTACs extends beyond oncology, with ongoing research and technological advancements needed to maximize their therapeutic potential. Future progress in this field relies on interdisciplinary collaboration and the integration of advanced computational tools to open new treatment avenues across various diseases.

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Section: Advanced Strategies For Protacsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety

Zhang,

Xie,

Ran

et al. 2024

Journal Cellular Physiology

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“…[19][20][21][22][23][24][25][26][27][28] TPD techniques rely on the ubiquitin-proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates. [29][30][31][32][33][34][35][36][37][38][39][40][41] The concept of PROTAC was first proposed in 2001, and the PROTAC technology has developed rapidly in the past 20 years. 5,8,19,[42][43][44][45] At the present, more than 10 PROTAC degraders have entered clinical Phase I-II trials with ARV-471 and ARV-110 from Arvinas, Inc as the most advanced ones for the treatment of recurrent breast cancer and prostate cancer, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…TPD has entered its third decade with both opportunities and challenges 19–28 . TPD techniques rely on the ubiquitin–proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates 29–41 …”

Section: Introductionmentioning

confidence: 99%

“… 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 TPD techniques rely on the ubiquitin–proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates. 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 …”

Section: Introductionmentioning

confidence: 99%

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PROTACs: A novel strategy for cancer drug discovery and development

Han

Sun

2023

MedComm

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Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: a small molecule that binds to a target protein, an E3 ligase ligand (consisting of an E3 ligase and its small molecule recruiter), and a chemical linker that hooks first two components together. In the past 20 years, we have witnessed advancement of multiple PRO-TAC degraders into the clinical trials for anticancer therapies. However, one of the major challenges of PROTAC technology is that only very limited number of E3 ligase recruiters are currently available as E3 ligand for targeted protein degradation (TPD), although human genome encodes more than 600 E3 ligases. Thus, there is an urgent need to identify additional effective E3 ligase recruiters for TPD applications. In this review, we summarized the existing RING-type E3 ubiquitin ligase and their small molecule recruiters that act as effective E3 ligands of PRO-TAC degraders and their application in anticancer drug discovery. We believe that this review could serve as a reference in future development of efficient E3 ligands of PROTAC technology for cancer drug discovery and development.

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Nanomotor‐Driven Targeting Chimeras as Accelerators for the Degradation of Extracellular Proteins

Ning,

Li,

Liu

et al. 2024

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Targeted protein degradation (TPD) is emerging as a therapeutic paradigm and a serviceable research tool in chemical biology and disease treatment. However, without driving sources, most targeting chimeras (TACs) lack the capability of self‐diffusion and active searching in biological environments, which significantly impedes degradation efficiency. Herein, nanomotor‐driven targeting chimeras (MotorTACs) are ingeniously designed to achieve effective internalization and degradation of extracellular platelet‐derived growth factor (PDGF), a driver to cancer invasion and metastasis. Catalyzed by endogenous H2O2, MotorTACs diffused rapidly and searched actively in living cells, as visualized at the single‐particle level under the dark‐field mode. Hydrolysis efficiency is significantly enhanced as target protein degradation is complete in only 4 h. Furthermore, MotorTACs‐mediated degradation of PDGF is found to be via the lysosome and ubiquitin‐proteasome dual‐degradation pathways. Taking advantage of the properties, it is anticipated that MotorTACs provide a unique strategy against extracellular undruggable proteins, thus advancing the development of therapeutic interventions in chemical biology and disease treatment.

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Discovery of selective platelet-derived growth factor receptor-beta (PDGFR-β) bifunctional small-molecule degraders

Cited by 8 publications

References 46 publications

Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety

Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety

PROTACs: A novel strategy for cancer drug discovery and development

Nanomotor‐Driven Targeting Chimeras as Accelerators for the Degradation of Extracellular Proteins

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