Discovery of a Potent and Selective Degrader for USP7

Yuan, Peng; Fu, Jingfeng; Shi, Yun-Kai; Zhang, Mengmeng; Luo, Guanghao; Luo, Xiaomin; Song, Ning; Tian, Mi; Yang, Yaxi; Li, Jia; Zhou, Yubo

doi:10.1002/anie.202204395

Cited by 27 publications

(19 citation statements)

References 63 publications

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“…USP7 is known to stabilize the oncogenic E3 ubiquitin ligase mouse double minute 2 homolog (MDM2) that promotes the proteasomal degradation of p53 [ 108 ]. A recent study revealed that the USP7-degrading proteolysis targeting chimera (PROTAC) maintained potent cell growth inhibition in p53 mutant cancer cells, suggesting USP7-PROTAC as a promising method for potential p53 mutant cancer therapy [ 109 ]. Polo-like kinase 1 (PLK1) is a master mitotic regulator regulating DNA damage, the G2/M checkpoint, cell death pathways, and replication stress response [ 110 ].…”

Section: Degradation Of Critical Proteins In Dna Damage Repair-mediat...mentioning

confidence: 99%

Protein degradation: expanding the toolbox to restrain cancer drug resistance

Hui

Jiang

et al. 2023

J Hematol Oncol

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Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain drug resistance has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib and proteolysis-targeting chimeric have been developed. Compared with intervention at the transcriptional level, targeting the degradation process seems to be a more rapid and direct strategy. Proteasomal proteolysis and lysosomal proteolysis are the most critical quality control systems responsible for the degradation of proteins or organelles. Although proteasomal and lysosomal inhibitors (e.g., bortezomib and chloroquine) have achieved certain improvements in some clinical application scenarios, their routine application in practice is still a long way off, which is due to the lack of precise targeting capabilities and inevitable side effects. In-depth studies on the regulatory mechanism of critical protein degradation regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), and chaperones, are expected to provide precise clues for developing targeting strategies and reducing side effects. Here, we discuss the underlying mechanisms of protein degradation in regulating drug efflux, drug metabolism, DNA repair, drug target alteration, downstream bypass signaling, sustaining of stemness, and tumor microenvironment remodeling to delineate the functional roles of protein degradation in drug resistance. We also highlight specific E3 ligases, DUBs, and chaperones, discussing possible strategies modulating protein degradation to target cancer drug resistance. A systematic summary of the molecular basis by which protein degradation regulates tumor drug resistance will help facilitate the development of appropriate clinical strategies.

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Section: Degradation Of Critical Proteins In Dna Damage Repair-mediat...mentioning

confidence: 99%

Protein degradation: expanding the toolbox to restrain cancer drug resistance

Hui

Jiang

et al. 2023

J Hematol Oncol

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“…When the PROTAC molecule binds to both the target protein and the E3 ubiquitin ligase, it brings them into close proximity, leading to the transfer of ubiquitin molecules from the E2 ubiquitin-conjugating enzyme to the target protein (Figure B). , The ubiquitinated target protein is then recognized and degraded by the proteasome, resulting in its elimination from the cell. PROTACs have shown great potential in preclinical and early clinical studies, and their unique mechanism of action offers advantages over traditional small-molecule inhibitors. , PROTACs act in an event-driven, substoichiometric, and catalytic manner, offering several advantages over traditional inhibitors in terms of increased potency and specificity, reduced resistance, and the potential to target previously “undruggable” proteins. , On the other hand, the combination of PROTACs with proteomics analysis has proven to be a successful method for identifying potential targets of inhibitors or natural products, indicating that PROTAC technology has become a powerful tool, not only for enhancing the potency of compounds but also for exploring their therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

Facilitated Drug Repurposing with Artemisinin-Derived PROTACs: Unveiling PCLAF as a Therapeutic Target

Zeng

Chen

et al. 2023

J. Med. Chem.

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Artemisinin, a prominent anti-malaria drug, is being investigated for its potential as a repurposed cancer treatment. However, its effectiveness in tumor cell lines remains limited, and its mechanism of action is unclear. To make more progress, the PROteolysis-TArgeting chimera (PROTAC) technique has been applied to design and synthesize novel artemisinin derivatives in this study. Among them, AD4, the most potent compound, exhibited an IC 50 value of 50.6 nM in RS4;11 cells, over 12-fold better than that of its parent compound, SM1044. This was supported by prolonged survival of RS4;11-transplanted NOD/SCID mice. Meanwhile, AD4 effectively degraded PCLAF in RS4;11 cells and thus activated the p21/Rb axis to exert antitumor activity by directly targeting PCLAF. The discovery of AD4 highlights the great potential of using PROTACs to improve the efficacy of natural products, identify therapeutic targets, and facilitate drug repurposing. This opens a promising avenue for transforming other natural products into effective therapies.

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“…Proteolytic targeted chimera (PROTAC), a rapidly emerging strategy, has evolved as a novel chemical method for selective proteins degradation. , In contrast to conventional occupancy-driven small-molecule inhibitors, PROTACs are event-driven and can eliminate kinase catalytic functions and non-kinase scaffolding functions. − Furthermore, PROTACs can function substoichiometrically and improve selectivity. , The PROTAC strategy targeting PLK4 is depicted in Figure B. PLK4 PROTAC consists of three parts: a warhead hijacking PLK4 protein, an E3 ligase binder specifically binding E3 ligase, and a linker conjugating these two moieties. , PLK4 PROTACs can result in polyubiquitination and the proteasomal degradation of PLK4.…”

Section: Introductionmentioning

confidence: 99%

“…Proteolytic targeted chimera (PROTAC), a rapidly emerging strategy, has evolved as a novel chemical method for selective proteins degradation. 36,37 In contrast to conventional occupancy-driven small-molecule inhibitors, PROTACs are eventdriven and can eliminate kinase catalytic functions and nonkinase scaffolding functions. 38−40 Furthermore, PROTACs can function substoichiometrically and improve selectivity.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of the First Potent, Selective, and In Vivo Efficacious Polo-like Kinase 4 Proteolysis Targeting Chimera Degrader for the Treatment of TRIM37-Amplified Breast Cancer

et al. 2023

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Polo-like kinase 4 (PLK4) is a master regulator of centriole replication and has been proposed as a therapeutic target for multiple cancers, especially TRIM37-amplified breast cancer. The development of novel and effective therapeutic strategies for TRIM37-amplified breast cancer therapy is challenging and extremely desirable. Herein, a structure−activity relationship (SAR) study with an emphasis on exploring different linker lengths and compositions was performed to report the discovery and characterization of SP27 as the first selective PLK4 proteolysis targeting chimera (PROTAC) degrader. SP27 exhibited effective PLK4 degradation, more potent inhibition of cell growth, and more efficient precision-therapeutic effect in the TRIM37-amplified MCF-7 cell line than conventional inhibitor CZS-035. Moreover, SP27 showed 149% bioavailability after intraperitoneal administration in PK studies and potent antitumor efficacy in vivo. The discovery of SP27 demonstrated the practicality and importance of PLK4 PROTAC and paved the way for studying PLK4-dependent biological functions and treat TRIM37-amplified breast cancer.

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Discovery of a Potent and Selective Degrader for USP7

Cited by 27 publications

References 63 publications

Protein degradation: expanding the toolbox to restrain cancer drug resistance

Protein degradation: expanding the toolbox to restrain cancer drug resistance

Facilitated Drug Repurposing with Artemisinin-Derived PROTACs: Unveiling PCLAF as a Therapeutic Target

Discovery of the First Potent, Selective, and In Vivo Efficacious Polo-like Kinase 4 Proteolysis Targeting Chimera Degrader for the Treatment of TRIM37-Amplified Breast Cancer

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