European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 251, С. 115248 - 115248
Опубликована: Март 7, 2023
Язык: Английский
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
168
European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 267, С. 116166 - 116166
Опубликована: Янв. 25, 2024
Язык: Английский
Процитировано
54
Acta Pharmaceutica Sinica B, Год журнала: 2024, Номер 14(10), С. 4266 - 4295
Опубликована: Апрель 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.
Язык: Английский
Процитировано
22
Journal of Medicinal Chemistry, Год журнала: 2022, Номер 65(16), С. 11066 - 11083
Опубликована: Авг. 8, 2022
Selective degradation of the cyclin-dependent kinases 12 and 13 (CDK12/13) presents a novel therapeutic opportunity for triple-negative breast cancer (TNBC), but there is still lack dual CDK12/13 degraders. Here, we report discovery first series highly potent selective degraders by employing proteolysis-targeting chimera (PROTAC) technology. The optimal compound 7f effectively degraded CDK12 CDK13 with DC50 values 2.2 2.1 nM, respectively, in MDA-MB-231 cells. Global proteomic profiling demonstrated target selectivity 7f. In vitro, suppressed expression core DNA damage response (DDR) genes time- dose-dependent manner. Further, markedly inhibited proliferation multiple TNBC cell lines including MFM223, an IC50 value 47 nM. Importantly, displayed significantly improved antiproliferative activity compared to structurally similar inhibitor 4, suggesting potential advantage degrader targeted therapy.
Язык: Английский
Процитировано
43
The Innovation, Год журнала: 2023, Номер 4(3), С. 100413 - 100413
Опубликована: Март 15, 2023
Targeted protein degradation (TPD) is emerging as a strategy to overcome the limitations of traditional small-molecule inhibitors. Proteolysis-targeting chimera (PROTAC) technology can be used target proteins by hijacking ubiquitin-proteasome system. Conceptually, PROTAC aims "undruggable" majority in human proteome. Through constant exploration and optimization PROTACs exploitation other TPD strategies over two decades, has expanded from theoretical studies clinical strategies, with practical applications oncological, immunological, diseases. In this review, we introduce mechanisms, features, molecular targets orthodox summarize drugs under study cancer therapeutics trials. We also discuss derivatives such lysosome-targeting chimeras, autophagy-targeting glue strategies. Collectively, summarized herein support full potential biomedical industry.
Язык: Английский
Процитировано
35
ChemBioChem, Год журнала: 2023, Номер 24(10)
Опубликована: Апрель 5, 2023
Degraders have illustrated that compound-induced proximity to E3 ubiquitin ligases can prompt the ubiquitination and degradation of disease-relevant proteins. Hence, this pharmacology is becoming a promising alternative complement available therapeutic interventions (e. g., inhibitors). rely on protein binding instead inhibition and, hence, they hold promise broaden druggable proteome. Biophysical structural biology approaches been cornerstone understanding rationalizing degrader-induced ternary complex formation. Computational models now started harness experimental data from these with aim identify rationally help design new degraders. This review outlines current computational strategies used study formation highlights importance effective crosstalk between in advancement targeted (TPD) field. As our molecular features govern drug-induced interactions grows, faster optimizations superior innovations for TPD other proximity-inducing modalities are sure follow.
Язык: Английский
Процитировано
33
Cell Insight, Год журнала: 2023, Номер 2(3), С. 100092 - 100092
Опубликована: Март 27, 2023
Proteolysis targeting chimera (PROTAC) degradation of pathogenic proteins by hijacking the ubiquitin-proteasome-system has become a promising strategy in drug design. The overwhelming advantages PROTAC technology have ensured rapid and wide usage, multiple PROTACs entered clinical trials. Several antiviral been developed with bioactivities against various viruses. However, number reported is far less than that other diseases, e.g., cancers, immune disorders, neurodegenerative possibly because common deficiencies (e.g., limited available ligands poor membrane permeability) plus complex mechanism involved high tendency viral mutation during transmission replication, which may challenge successful development effective PROTACs. This review highlights important advances this rapidly growing field critical limitations encountered developing analyzing current status representative examples PROTAC-like agents. We also summarize analyze general principles strategies for design optimization intent indicating potential strategic directions future progress.
Язык: Английский
Процитировано
32
Molecular Diversity, Год журнала: 2023, Номер 28(1), С. 309 - 333
Опубликована: Фев. 15, 2023
Язык: Английский
Процитировано
22
Translational Oncology, Год журнала: 2024, Номер 41, С. 101893 - 101893
Опубликована: Янв. 29, 2024
Triple-negative breast cancer (TNBC) is a subtype of with poor prognosis. The number cases increased by 2.26 million in 2020, making it the most commonly diagnosed type world. TNBCs lack hormone receptor (HR) and human epidermal growth factor 2 (HER2), which limits treatment options. Currently, paclitaxel-based drugs combined other chemotherapeutics remain main for TNBC. There currently no consensus on best therapeutic regimen However, there have been successful clinical trials exploring large-molecule monoclonal antibodies, small-molecule targeted drugs, novel antibody-drug conjugate (ADC). Although antibodies produced success, their large molecular weight can limit benefits. It worth noting that past 30 years, FDA has approved small molecule HER2-positive cancers. effective targets occurrence drug resistance pose significant challenges To improve prognosis TNBC, crucial to search overcome resistance. This review examines efficacy, adverse effects, mechanisms, potential solutions both monotherapies combination therapies. New targets, including nuclear export protein 1 (XPO1) hedgehog (Hh), are emerging as options researchers become integrated into Additionally, growing interest degradation chimeras (PROTACs), degraders rogue proteins, future therapy direction. provides potentially valuable insights implications.
Язык: Английский
Процитировано
12
Frontiers in Oncology, Год журнала: 2024, Номер 14
Опубликована: Апрель 18, 2024
Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its propensity for metastasis and poor prognosis. TNBC evades the body's immune system recognition attack through various mechanisms, including Janus Kinase 2 (JAK2)/signal transducer activator of transcription 3 (STAT3) signaling pathway. This pathway, characterized by heightened activity in numerous solid tumors, exhibits pronounced activation specific subtypes. Consequently, targeting JAK2/STAT3 pathway emerges as promising precise therapeutic strategy TNBC. The signal transduction cascade predominantly involves receptor tyrosine kinases, kinase JAK2, factor STAT3. Ongoing preclinical studies research are actively investigating this potential target treatment. article comprehensively reviews investigations into treatment using small molecule compounds. review explores role therapeutics, evaluating benefits limitations active inhibitors proteolysis-targeting chimeras aim is facilitate development novel small-molecule compounds that effectively. Ultimately, work seeks contribute enhancing efficacy patients with
Язык: Английский
Процитировано
6