Applications of protein ubiquitylation and deubiquitylation in drug discovery DOI Creative Commons
Yilin Chen, Haoan Xue, Jianping Jin

и другие.

Journal of Biological Chemistry, Год журнала: 2024, Номер 300(5), С. 107264 - 107264

Опубликована: Апрель 5, 2024

The ubiquitin-proteasome system (UPS) is the major machinery mediating specific protein turnover in eukaryotic cells. By ubiquitylating unwanted, damaged, or harmful proteins and driving their degradation, UPS involved many important cellular processes. Several new UPS-based technologies, including molecular glue degraders PROTACs (Proteolysis-targeting chimeras) to promote DUBTACs (deubiquitinase-targeting increase stability, have been developed. specifically inducing interactions between different ubiquitin ligases targeted that are not otherwise related, degrade via system; contrast, by proximity of deubiquitinases, created clear degradable polyubiquitin chains stabilize proteins. In this review, we summarize recent research progress degraders, PROTACs, applications. We discuss immunomodulatory drugs (IMiDs), sulfonamides, CDK-targeting development PROTACs. also introduce principle DUBTAC its Finally, propose a few future directions these three technologies related homeostasis.

Язык: Английский

PROTACs: past, present and future DOI
Ke Li, Craig M. Crews

Chemical Society Reviews, Год журнала: 2022, Номер 51(12), С. 5214 - 5236

Опубликована: Янв. 1, 2022

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of one ligand that binds to a protein interest (POI) and another can recruit an E3 ubiquitin ligase. The chemically-induced proximity between the POI ligase results in ubiquitination subsequent degradation by ubiquitin-proteasome system (UPS). event-driven mechanism action (MOA) PROTACs offers several advantages compared traditional occupancy-driven small molecule inhibitors, such as catalytic nature, reduced dosing frequency, more potent longer-lasting effect, added layer selectivity reduce potential toxicity, efficacy face drug-resistance mechanisms, targeting nonenzymatic functions, expanded target space. Here, we highlight important milestones briefly discuss lessons learned about targeted (TPD) recent years conjecture on efforts still needed expand toolbox for PROTAC discovery ultimately provide promising therapeutics.

Язык: Английский

Процитировано

426
Protein degraders enter the clinic — a new approach to cancer therapy DOI

Deborah Chirnomas,

Keith R. Hornberger, Craig M. Crews

и другие.

Nature Reviews Clinical Oncology, Год журнала: 2023, Номер 20(4), С. 265 - 278

Опубликована: Фев. 13, 2023

Язык: Английский

Процитировано

348
Cell cycle on the crossroad of tumorigenesis and cancer therapy DOI Creative Commons
Jing Liu, Yunhua Peng, Wenyi Wei

и другие.

Trends in Cell Biology, Год журнала: 2021, Номер 32(1), С. 30 - 44

Опубликована: Июль 22, 2021

Язык: Английский

Процитировано

267
Aptamer‐PROTAC Conjugates (APCs) for Tumor‐Specific Targeting in Breast Cancer DOI
Shipeng He, Fei Gao,

Junhui Ma

и другие.

Angewandte Chemie International Edition, Год журнала: 2021, Номер 60(43), С. 23299 - 23305

Опубликована: Июль 9, 2021

Development of proteolysis targeting chimeras (PROTACs) is emerging as a promising strategy for targeted protein degradation. However, the drug development using heterobifunctional PROTAC molecules generally limited by poor membrane permeability, low in vivo efficacy and indiscriminate distribution. Herein an aptamer-PROTAC conjugation approach was developed novel to improve tumor-specific ability antitumor potency conventional PROTACs. As proof concept, first conjugate (APC) designed conjugating BET-targeting nucleic acid aptamer AS1411 (AS) via cleavable linker. Compared with unmodified BET PROTAC, molecule (APR) showed improved tumor MCF-7 xenograft model, leading enhanced degradation decreased toxicity. Thus, APC may pave way design PROTACs have broad applications PROTAC-based drugs.

Язык: Английский

Процитировано

195
TF-PROTACs Enable Targeted Degradation of Transcription Factors DOI
Jing Liu, He Chen, H. Ümit Kanıskan

и другие.

Journal of the American Chemical Society, Год журнала: 2021, Номер 143(23), С. 8902 - 8910

Опубликована: Июнь 8, 2021

Transcription factors (TFs) represent a major class of therapeutic targets for the treatment human diseases including cancer. Although biological functions and even crystal structures many TFs have been clearly elucidated, there is still no viable approach to target majority TFs, thus rendering them undruggable decades. PROTACs (proteolysis targeting chimeras) emerge as powerful modalities, which rely on induced protein–protein interactions between proteins interest (POIs) E3 ubiquitin ligases aid degradation POIs by ubiquitin-proteasome system (UPS). Here, we report development platform termed TF-PROTAC, links an DNA oligonucleotide ligase ligand via click reaction, selectively degrade TF interest. The selectivity these TF-PROTACs depends oligonucleotides utilized that can be specific We developed two series VHL-based TF-PROTACs, NF-κB-PROTAC (dNF-κB) E2F-PROTAC (dE2F), effectively endogenous p65 E2F1 in cells, respectively, subsequently display superior antiproliferative effects cells. Collectively, our results suggest provide generalizable achieve selective universal strategy most "undruggable" TFs.

Язык: Английский

Процитировано

178
Chemistries of bifunctional PROTAC degraders DOI
Chao-Guo Cao,

Ming He,

Liguo Wang

и другие.

Chemical Society Reviews, Год журнала: 2022, Номер 51(16), С. 7066 - 7114

Опубликована: Янв. 1, 2022

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

Язык: Английский

Процитировано

175
PROTACs: great opportunities for academia and industry (an update from 2020 to 2021) DOI Creative Commons

Ming He,

Chao-Guo Cao, Zhihao Ni

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Июнь 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.

Язык: Английский

Процитировано

174
Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation DOI
Yu Chen, Ira Tandon, William J. Heelan

и другие.

Chemical Society Reviews, Год журнала: 2022, Номер 51(13), С. 5330 - 5350

Опубликована: Янв. 1, 2022

This tutorial review discusses the convergence of drug delivery systems and PROTACs, surveys burgeoning PROTAC strategies, summarizes their design principles, clarifies challenges, outlooks future translational opportunities.

Язык: Английский

Процитировано

142
Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders DOI Creative Commons
Claudia J. Diehl, Alessio Ciulli

Chemical Society Reviews, Год журнала: 2022, Номер 51(19), С. 8216 - 8257

Опубликована: Янв. 1, 2022

This review provides a comprehensive overview of the structure-based design small-molecule VHL ligands and their applications as inhibitors E3 ligase recruiting moieties in PROTAC degraders.

Язык: Английский

Процитировано

127
Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy DOI Creative Commons
Jing Gao, Bo Hou,

Qiwen Zhu

и другие.

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Июль 26, 2022

Abstract PROteolysis TArgeting Chimeras (PROTACs) has been exploited to degrade putative protein targets. However, the antitumor performance of PROTACs is impaired by their insufficient tumour distribution. Herein, we present de novo designed polymeric PROTAC (POLY-PROTAC) nanotherapeutics for tumour-specific degradation. The POLY-PROTACs are engineered covalently grafting small molecular onto backbone an amphiphilic diblock copolymer via disulfide bonds. self-assemble into micellar nanoparticles and sequentially respond extracellular matrix metalloproteinase-2, intracellular acidic reductive microenvironment. POLY-PROTAC NPs further functionalized with azide groups bioorthogonal click reaction-amplified delivery tissue. For proof-of-concept, demonstrate that BRD4 degradation nanoplatform combine photodynamic therapy efficiently regress xenografts in a mouse model MDA-MB-231 breast cancer. This study suggests potential precise PROTAC-based cancer therapy.

Язык: Английский

Процитировано

119