Targeting HER2-positive breast cancer: advances and future directions

Nature Reviews Drug Discovery, Год журнала: 2022, Номер 22(2), С. 101 - 126

Опубликована: Ноя. 7, 2022

Язык: Английский

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PROTACs: past, present and future

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

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Targeted protein degradation: mechanisms, strategies and application

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

Опубликована: Апрель 4, 2022

Abstract Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application activity modulators, particularly inhibitors, has been the mainstream in development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology emerged as one most promising approaches to remove specific disease-associated proteins by exploiting cells’ own destruction machinery. addition PROTAC, many different targeted degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), Antibody-based PROTAC (AbTAC), are emerging. These technologies have only greatly expanded scope TPD, also provided fresh insights into discovery. Here, we summarize advances major TPD technologies, discuss their potential applications, hope provide a prime for both biologists chemists who interested this vibrant field.

Язык: Английский

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

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

Опубликована: Фев. 13, 2023

Язык: Английский

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Molecular targeted therapy for anticancer treatment

Experimental & Molecular Medicine, Год журнала: 2022, Номер 54(10), С. 1670 - 1694

Опубликована: Окт. 12, 2022

Abstract Since the initial clinical approval in late 1990s and remarkable anticancer effects for certain types of cancer, molecular targeted therapy utilizing small molecule agents or therapeutic monoclonal antibodies acting as signal transduction inhibitors has served a fundamental backbone precision medicine cancer treatment. These approaches are now used clinically first-line various human cancers. Compared to conventional chemotherapy, have efficient with fewer side effects. However, emergence drug resistance is major drawback therapy, several strategies been attempted improve efficacy by overcoming such resistance. Herein, we summarize current knowledge regarding agents, including classification, brief biology target kinases, mechanisms action, examples perspectives future development.

Язык: Английский

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Exploring the next generation of antibody–drug conjugates

Nature Reviews Clinical Oncology, Год журнала: 2024, Номер 21(3), С. 203 - 223

Опубликована: Янв. 8, 2024

Язык: Английский

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Chemistries of bifunctional PROTAC degraders

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

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

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

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Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation

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

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The evolving role of investigative toxicology in the pharmaceutical industry

Nature Reviews Drug Discovery, Год журнала: 2023, Номер 22(4), С. 317 - 335

Опубликована: Фев. 13, 2023

For decades, preclinical toxicology was essentially a descriptive discipline in which treatment-related effects were carefully reported and used as basis to calculate safety margins for drug candidates. In recent years, however, technological advances have increasingly enabled researchers gain insights into toxicity mechanisms, supporting greater understanding of species relevance translatability humans, prediction events, mitigation side development biomarkers. Consequently, investigative (or mechanistic) has been gaining momentum is now key capability the pharmaceutical industry. Here, we provide an overview current status field using case studies discuss potential impact ongoing developments, based on survey toxicologists from 14 European-based medium-sized large companies. Investigative tools strategies are companies reduce safety-related attrition development. This Perspective article summarizes goals toxicology, highlights approaches discusses selected emerging technologies that improve safety-testing paradigm.

Язык: Английский

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