Photoswitchable PROTACs for Reversible and Spatiotemporal Regulation of NAMPT and NAD+ DOI

Junfei Cheng,

Jing Zhang, Shipeng He

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(12)

Published: Jan. 29, 2024

Abstract Nicotinamide adenine dinucleotide (NAD + ) is an essential coenzyme with diverse biological functions in DNA synthesis. phosphoribosyltransferase (NAMPT) a key rate‐limiting enzyme involved NAD biosynthesis mammals. We developed the first chemical tool for optical control of NAMPT and systems using photoswitchable proteolysis‐targeting chimeras (PS‐PROTACs). An activator dimethylpyrazolazobenzene photoswitch were used to design highly efficient PS‐PROTACs, enabling up‐ down‐reversible regulation light‐dependent manner reducing toxicity associated inhibitor‐based PS‐PROTACs. PS‐PROTAC was activated under 620 nm irradiation, realizing vivo manipulation antitumor activity, NAMPT, .

Language: Английский

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021) DOI Creative Commons

Ming He,

Chao-Guo Cao, Zhihao Ni

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: June 9, 2022

Abstract PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through ubiquitin–proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such cancer, immune disorders, viral infections, neurodegenerative diseases, but also provide unique chemical knockdown tools biological research catalytic, reversible, rapid manner. In 2019, our group published review article “PROTACs: great opportunities academia industry” journal, summarizing representative compounds reported before end 2019. past 2 years, entire field protein experienced development, including large increase number papers on small-molecule degraders have entered will enter stage. addition PROTAC molecular glue technology, other technologies are developing rapidly. this article, we mainly summarize related targets 2020–2021 present researchers exciting developments degradation. The problems need solved briefly introduced.

Language: Английский

Citations

174
Chemistries of bifunctional PROTAC degraders DOI
Chao-Guo Cao,

Ming He,

Liguo Wang

et al.

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(16), P. 7066 - 7114

Published: Jan. 1, 2022

Proteolysis targeting chimeras (PROTACs) technology is a novel and promising therapeutic strategy using small molecules to induce ubiquitin-dependent degradation of proteins.

Language: Английский

Citations

170
An overview of PROTACs: a promising drug discovery paradigm DOI Creative Commons

Liu Zi,

Mingxing Hu,

Yang Yu

et al.

Molecular Biomedicine, Journal Year: 2022, Volume and Issue: 3(1)

Published: Dec. 20, 2022

Abstract Proteolysis targeting chimeras (PROTACs) technology has emerged as a novel therapeutic paradigm in recent years. PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin–proteasome system. Currently, about 20–25% of all protein targets being studied, and most works focus on their enzymatic functions. Unlike small molecules, inhibit whole biological function binding to inducing subsequent proteasomal degradation. compensate for limitations transcription factors, nuclear proteins, other scaffolding difficult handle with traditional small-molecule inhibitors. have successfully degraded diverse such BTK, BRD4, AR, ER, STAT3, IRAK4, tau, etc. And ARV-110 ARV-471 exhibited excellent efficacy clinical II trials. However, what appropriate PROTAC achieve better benefits than inhibitors not fully understood. how rationally design an efficient optimize it be orally effective poses big challenges researchers. In this review, we summarize features technology, analyze detail general principles designing PROTACs, discuss typical application different categories. addition, also introduce progress relevant trial results representative assess may face. Collectively, our studies provide references further PROTACs.

Language: Английский

Citations

156
Emerging degrader technologies engaging lysosomal pathways DOI Creative Commons
Yu Ding, Dong Xing, Yiyan Fei

et al.

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(21), P. 8832 - 8876

Published: Jan. 1, 2022

ATTECs and several other emerging degrader technologies hijacking the lysosomal pathways greatly expand spectrum of degradable targets provide new opportunities for targeted drug discovery.

Language: Английский

Citations

77
Characteristic roadmap of linker governs the rational design of PROTACs DOI Creative Commons
Yawen Dong, Tingting Ma, Ting Xu

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(10), P. 4266 - 4295

Published: April 11, 2024

Proteolysis targeting chimera (PROTAC) technology represents a groundbreaking development in drug discovery, leveraging the ubiquitin‒proteasome system to specifically degrade proteins responsible for disease. PROTAC is characterized by its unique heterobifunctional structure, which comprises two functional domains connected linker. The linker plays pivotal role determining PROTAC's biodegradative efficacy. Advanced and rationally designed linkers are under development. Nonetheless, correlation between characteristics efficacy remains under-investigated. Consequently, this study will present multidisciplinary analysis of their impact on efficacy, thereby guiding rational design linkers. We primarily discuss structural types linkers, optimization strategies used design. Furthermore, we how factors like length, group type, flexibility, linkage site affect biodegradation efficiency PROTACs. believe that work contribute towards advancement research area.

Language: Английский

Citations

24
Insight into Recent Advances in Degrading Androgen Receptor for Castration-Resistant Prostate Cancer DOI Open Access
Qiao‐Hong Chen, Erick Munoz,

Dennis Ashong

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(3), P. 663 - 663

Published: Feb. 4, 2024

Induced protein degradation has emerged as an innovative drug discovery approach, complementary to the classical method of suppressing function. The androgen receptor signaling pathway been identified primary driving force in development and progression lethal castration-resistant prostate cancer. Since degraders function differently from antagonists, they hold promise overcome resistance challenges faced by current therapeutics. Proteolysis-targeting chimeras (PROTACs), monomeric degraders, hydrophobic tagging, molecular glues, autophagic have demonstrated their capability downregulating intracellular concentrations. potential these treat cancer is substantiated advancement six PROTACs two into phase I or II clinical trials. Although chemical structures, vitro vivo data, mechanisms reviewed, it crucial stay updated on recent advances this field novel new strategies continue emerge. This review thus provides insight advancements paradigm, offering overview progress made since 2020.

Language: Английский

Citations

17
Targeting intracellular cancer proteins with tumor‐microenvironment‐responsive bispecific nanobody‐PROTACs for enhanced therapeutic efficacy DOI Creative Commons
Changping Deng, Jiacheng Ma, Yuping Liu

et al.

MedComm, Journal Year: 2025, Volume and Issue: 6(2)

Published: Jan. 19, 2025

Abstract Proteolysis targeting chimeras (PROTACs) are pivotal in cancer therapy for their ability to degrade specific proteins. However, non‐specificity can lead systemic toxicity due protein degradation normal cells. To address this, we have integrated a nanobody into the PROTACs framework and leveraged tumor microenvironment enhance drug specificity. In this study, engineered BumPeD, novel bispecific nanobody‐targeted PROTACs‐like platform, by fusing two nanobodies with Furin protease cleavage site (RVRR) degron sequence (ALAPYIP or KIGLGRQKPPKATK), enabling direct of intracellular We utilized KN035 Nb4A target PD‐L1 (programmed death ligand 1) on cell surface Survivin, respectively. vitro experiments showed that BumPeD triggers Survivin via ubiquitin‐proteasome pathway, inducing apoptosis suppressing bladder proliferation migration. vivo further confirmed BumPeD's robust anti‐tumor efficacy, underscoring its potential as precise strategy therapy. Our platform provides systematic approach developing effective practical degraders, offering targeted theoretical basis experimental support development degradative drugs, well new directions

Language: Английский

Citations

2
Progress and Challenges in Targeted Protein Degradation for Neurodegenerative Disease Therapy DOI
Yingxu Fang, Jiaxing Wang, Min Zhao

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(17), P. 11454 - 11477

Published: Aug. 25, 2022

Neurodegenerative diseases (NDs) are currently incurable that cause progressive degeneration of nerve cells. Many the disease-causing proteins NDs "undruggable" for traditional small-molecule inhibitors (SMIs). None compounds attenuated amyloid-β (Aβ) accumulation process have entered clinical practice, and many phase III trials SMIs Alzheimer's disease (AD) failed. In recent years, emerging targeted protein degradation (TPD) technologies such as proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimaeras (LYTACs), autophagy-targeting (AUTACs) with TPD-assistive click-formed (CLIPTACs) deubiquitinase-targeting chimera (DUBTAC) developed rapidly. vitro in vivo experiments also confirmed TPD technology can target ND pathogenic proteins, bringing hope treatment NDs. Herein, we review latest technologies, introduce their targets technical characteristics, discuss potential research, providing a new perspective development field.

Language: Английский

Citations

49
PROTAC degraders with ligands recruiting MDM2 E3 ubiquitin ligase: an updated perspective DOI Creative Commons
Xin Han, Wenyi Wei, Yi Sun

et al.

Acta Materia Medica, Journal Year: 2022, Volume and Issue: 1(2)

Published: Jan. 1, 2022

Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase which effectively degrades tumor suppressor p53. In the past two decades, many MDM2 inhibitors that disrupt MDM2-p53 binding have been discovered and developed. Given forms auto-regulatory loop in p53 a substrate of for targeted degradation, while target transcriptional upregulation, these limited efficacy due to degradation by accumulated upon rapid vivo clearance inhibitors. Fortunately, proteolysis targeting chimeras (PROTACs), novel therapeutic strategy, overcome limitations Some developed decades used PROTAC technology applications: 1) as component 1 bind with endogenous PROTAC-based MDM2; 2) ligand other oncogenic proteins. this review, we summarize current progress discovery development MDM2-based drugs future perspectives challenges their applications effective treatment human cancer.

Language: Английский

Citations

47
Strategies for the discovery of oral PROTAC degraders aimed at cancer therapy DOI Creative Commons
Xin Han, Yi Sun

Cell Reports Physical Science, Journal Year: 2022, Volume and Issue: 3(10), P. 101062 - 101062

Published: Sept. 21, 2022

In the past two decades, we have witnessed discovery and development of many potent efficacious proteolysis-targeting chimera (PROTAC) degraders, with several in phase I/II clinical trials. However, achieving good oral bioavailability for these degraders remains one biggest challenges, given fact that PROTACs are often "beyond rule 5" small-molecule drugs because their higher molecular weight other poor physiochemical properties. this review, focus on current efforts various orally available anti-cancer PROTAC comprehensively summarize strategies applied to end. We believe summarized here may provide a reference future new oral-available treatment human diseases.

Language: Английский

Citations

46