Non-enzymatic protein targeting agents as a promising strategy for cancer treatment DOI Creative Commons

M. Ambrose,

Jin-Hyung Lee, Aleem Syed

et al.

Frontiers in Drug Discovery, Journal Year: 2025, Volume and Issue: 5

Published: Jan. 29, 2025

Increased research attention has been brought to non-enzymatic protein targeting agents as a new and effective strategy for advancing cancer treatment. To discover this class of anticancer drugs, two molecular approaches the activities proteins have shown promising experimental, preclinical, clinical results. In first approach, selective known PROteolysis-TArgeting Chimeras (PROTACs) employ innate endogenous degradation machinery in cells proteolyze targeted protein. The combination highly PROTACs exploitation cellular pathways provides opportunity treat diseases that were previously deemed incurable due lack enzymatic proteins. second approach targets protein-protein interactions (PPIs) an alternative route alters functional complexes thus significantly influence cell fitness survival. efficiently identify potential chemical leads these approaches, high-throughput screening (HTS) extremely valuable its ability quickly screen large libraries compounds. review paper, we will provide overview developing anti-cancer impact inhibitors.

Language: Английский

Targeting p53 pathways: mechanisms, structures and advances in therapy DOI Creative Commons

Haolan Wang,

Ming Guo,

Hudie Wei

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 1, 2023

The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. p53 protein transcription factor that can activate expression multiple target genes plays critical roles regulating cell cycle, apoptosis, genomic stability, widely regarded as "guardian genome". Accumulating evidence shown also regulates metabolism, ferroptosis, microenvironment, autophagy so on, all which contribute to suppression. Mutations not only impair its function, but confer oncogenic properties mutants. Since mutated inactivated malignant tumors, it very attractive for developing new anti-cancer drugs. However, until recently, was considered an "undruggable" little progress made with p53-targeted therapies. Here, we provide systematic review diverse molecular mechanisms signaling pathway how mutations impact progression. We discuss key structural features inactivation by mutations. In addition, efforts have therapies, challenges encountered clinical development.

Language: Английский

Citations

389
Targeted protein degradation: from mechanisms to clinic DOI
Jonathan M. Tsai, Radosław P. Nowak, Benjamin L. Ebert

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(9), P. 740 - 757

Published: April 29, 2024

Language: Английский

Citations

98
Targeted protein degrader development for cancer: advances, challenges, and opportunities DOI Creative Commons
Yuan Fang, Shuhang Wang,

Songzhe Han

et al.

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(5), P. 303 - 317

Published: April 13, 2023

Anticancer-targeted therapies inhibit various kinases implicated in cancer and have been used clinical settings for decades. However, many cancer-related targets are proteins without catalytic activity difficult to target using traditional occupancy-driven inhibitors. Targeted protein degradation (TPD) is an emerging therapeutic modality that has expanded the druggable proteome treatment. With entry of new-generation immunomodulatory drugs (IMiDs), selective estrogen receptor degraders (SERDs), proteolysis-targeting chimera (PROTAC) into trials, field TPD seen explosive growth past 10 years. Several challenges remain need be tackled increase successful translation drugs. We present overview global landscape trials over decade summarize profiles In addition, we highlight opportunities development effective future translation.

Language: Английский

Citations

48
Targeted protein degradation: advances in drug discovery and clinical practice DOI Creative Commons
Guangcai Zhong, Xiaoyu Chang, Weilin Xie

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 6, 2024

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

Language: Английский

Citations

22
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

48
Degradation of neurodegenerative disease-associated TDP-43 aggregates and oligomers via a proteolysis-targeting chimera DOI Creative Commons
Yu-Ling Tseng,

Po-Chao Lu,

Chi-Chang Lee

et al.

Journal of Biomedical Science, Journal Year: 2023, Volume and Issue: 30(1)

Published: April 26, 2023

Amyotrophic lateral sclerosis (ALS) associated with TAR DNA-binding protein 43 (TDP-43) aggregation has been considered as a lethal and progressive motor neuron disease. Recent studies have shown that both C-terminal TDP-43 (C-TDP-43) aggregates oligomers were neurotoxic pathologic agents in ALS frontotemporal lobar degeneration (FTLD). However, misfolding long an undruggable target by applying conventional inhibitors, agonists, or antagonists. To provide this unmet medical need, we aim to degrade these proteins designing series of proteolysis targeting chimeras (PROTACs) against C-TDP-43.By filter trap assay, western blotting, microscopy imaging, the degradation efficiency C-TDP-43 was studied Neuro-2a cells overexpressing eGFP-C-TDP-43 mCherry-C-TDP-43. The cell viability characterized alarmarBlue assay. beneficial disaggregating effects PROTAC examined YFP-C-TDP-43 transgenic C. elegans motility assay confocal microscopy. impact on oligomeric intermediates monitored fluorescence lifetime imaging size exclusion chromatography co-expressing mCherry-C-TDP-43.Four PROTACs different linker lengths synthesized characterized. Among chimeras, 2 decreased relieved C-TDP-43-induced cytotoxicity without affecting endogenous TDP-43. We showed bound E3 ligase initiate ubiquitination proteolytic degradation. By advanced microscopy, it further compactness population oligomers. In addition cellular model, also improved reducing nervous system.Our study demonstrated dual-targeting capacity newly-designed reduce their neurotoxicity, which shed light potential drug development for well other neurodegenerative diseases.

Language: Английский

Citations

32
Discovery of ARD-2051 as a Potent and Orally Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer DOI
Xin Han, Lijie Zhao,

Weiguo Xiang

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(13), P. 8822 - 8843

Published: June 29, 2023

We report the discovery of ARD-2051 as a potent and orally efficacious androgen receptor (AR) proteolysis-targeting chimera degrader. achieves DC50 values 0.6 nM Dmax >90% in inducing AR protein degradation both LNCaP VCaP prostate cancer cell lines, potently effectively suppresses AR-regulated genes, inhibits growth. good oral bioavailability pharmacokinetic profile mouse, rat, dog. A single dose strongly reduces gene expression xenograft tumor tissue mice. Oral administration growth causes no signs toxicity is promising degrader for advanced preclinical development treatment AR+ human cancers.

Language: Английский

Citations

29
PROTACs: A novel strategy for cancer drug discovery and development DOI Creative Commons
Xin Han, Yi Sun

MedComm, Journal Year: 2023, Volume and Issue: 4(3)

Published: May 29, 2023

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: small molecule that binds to target protein, an E3 ligase ligand (consisting and its recruiter), chemical linker hooks first two components together. In the past 20 years, we have witnessed advancement multiple degraders into clinical trials anticancer therapies. However, one major challenges is only very limited number recruiters are currently available as targeted protein degradation (TPD), although human genome encodes more than 600 ligases. Thus, there urgent need identify additional effective TPD applications. this review, summarized existing RING-type ubiquitin their act ligands application discovery. We believe review could serve reference future development efficient cancer discovery development.

Language: Английский

Citations

25
Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases DOI Creative Commons
Priyanka Dey Talukdar, Urmi Chatterji

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Nov. 13, 2023

Abstract Specific cell states in metazoans are established by the symphony of gene expression programs that necessitate intricate synergic interactions between transcription factors and co-activators. Deregulation these regulatory molecules is associated with state transitions, which turn accountable for diverse maladies, including developmental disorders, metabolic most significantly, cancer. A decade back factors, key enablers disease development, were historically viewed as ‘undruggable’; however, intervening years, a wealth literature validated they can be targeted indirectly through transcriptional co-activators, their confederates various physiological molecular processes. These along have ability to initiate modulate genes necessary normal functions, whereby, deregulation such may foster tissue-specific phenotype. Hence, it essential analyze how co-activators specific multilateral processes coordination other factors. The proposed review attempts elaborate an in-depth account involvement regulation, context-specific contributions pathophysiological conditions. This also addresses issue has not been dealt comprehensive manner hopes direct attention towards future research will encompass patient-friendly therapeutic strategies, where drugs targeting enhanced benefits reduced side effects. Additional insights into currently available interventions constraints eventually reveal multitudes advanced targets aiming amelioration good patient prognosis.

Language: Английский

Citations

24
p53/MDM2 signaling pathway in aging, senescence and tumorigenesis DOI
Youyi Huang, Xiaofang Che, Peter Wang

et al.

Seminars in Cancer Biology, Journal Year: 2024, Volume and Issue: 101, P. 44 - 57

Published: May 17, 2024

Language: Английский

Citations

14