Computer Methods and Programs in Biomedicine, Journal Year: 2025, Volume and Issue: 264, P. 108687 - 108687
Published: Feb. 27, 2025
Language: Английский
Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(5), P. 2699 - 2804
Published: Feb. 29, 2024
The ability to gain spatiotemporal information, and in some cases achieve control, the context of drug delivery makes theranostic fluorescent probes an attractive intensely investigated research topic. This interest is reflected steep rise publications on topic that have appeared over past decade. Theranostic probes, their various incarnations, generally comprise a fluorophore linked masked drug, which released as result certain stimuli, with both intrinsic extrinsic stimuli being reported. release then signaled by emergence signal. Importantly, use appropriate fluorophores has enabled not only this emerging fluorescence marker for but also provided modalities useful photodynamic, photothermal, sonodynamic therapeutic applications. In review we highlight recent work particular focus are activated tumor microenvironments. We summarize efforts develop other applications, such neurodegenerative diseases antibacterials. celebrates diversity designs reported date, from discrete small-molecule systems nanomaterials. Our aim provide insights into potential clinical impact still-emerging direction.
Language: Английский
Citations
139
Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)
Published: May 21, 2024
Abstract Proteolysis-targeting chimeras (PROTACs) technology has garnered significant attention over the last 10 years, representing a burgeoning therapeutic approach with potential to address pathogenic proteins that have historically posed challenges for traditional small-molecule inhibitors. PROTACs exploit endogenous E3 ubiquitin ligases facilitate degradation of interest (POIs) through ubiquitin–proteasome system (UPS) in cyclic catalytic manner. Despite recent endeavors advance utilization clinical settings, majority fail progress beyond preclinical phase drug development. There are multiple factors impeding market entry PROTACs, insufficiently precise favorable POIs standing out as one most formidable obstacles. Recently, there been exploration new-generation advanced including PROTAC prodrugs, biomacromolecule-PROTAC conjugates, and nano-PROTACs, improve vivo efficacy PROTACs. These improved possess capability mitigate undesirable physicochemical characteristics inherent thereby enhancing their targetability reducing off-target side effects. The will mark pivotal turning point realm targeted protein degradation. In this comprehensive review, we meticulously summarized state-of-the-art advancements achieved by these cutting-edge elucidated underlying design principles, deliberated upon prevailing encountered, provided an insightful outlook on future prospects within field.
Language: Английский
Citations
33
European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 261, P. 115793 - 115793
Published: Sept. 7, 2023
Language: Английский
Citations
37
Science Bulletin, Journal Year: 2023, Volume and Issue: 68(10), P. 1069 - 1085
Published: April 27, 2023
Language: Английский
Citations
36
Bioorganic & Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 88-89, P. 117334 - 117334
Published: May 18, 2023
Over the last two decades, proteolysis targeting chimeras (PROTACs) have been revolutionary in drug development rendering targeted protein degradation (TPD) as an emerging therapeutic modality. These heterobifunctional molecules are comprised of three units: a ligand for interest (POI), E3 ubiquitin ligase, and linker that tethers motifs together. Von Hippel-Lindau (VHL) is one most widely employed ligases PROTACs due to its prevalent expression across tissue types well-characterised ligands. Linker composition length has proven play important role determining physicochemical properties spatial orientation POI-PROTAC-E3 ternary complex, thus influencing bioactivity degraders. Numerous articles reports published showcasing medicinal chemistry aspects design, but few focused on around tethering linkers ligase In this review, we focus current synthetic strategies assembly VHL-recruiting PROTACs. We aim cover range fundamental chemistries used incorporate varying length, functionality.
Language: Английский
Citations
35
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
Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(4), P. 2466 - 2486
Published: Feb. 5, 2024
Adenoviral E1A binding protein 300 kDa (p300) and its closely related paralog CREB (CBP) are promising therapeutic targets for human cancer. Here, we report the first discovery of novel potent small-molecule PROTAC degraders p300/CBP against hepatocellular carcinoma (HCC), one most common solid tumors. Based upon clinical bromodomain inhibitor CCS1477, a conformational restriction strategy was used to optimize linker generate series PROTACs, culminating in identification QC-182. This compound effectively induces degradation SK-HEP-1 HCC cells dose-, time-, ubiquitin-proteasome system-dependent manner. QC-182 significantly downregulates p300/CBP-associated transcriptome cells, leading more cell growth inhibition compared parental inhibitors reported degrader dCBP-1. Notably, potently depletes proteins mouse xenograft tumor tissue. is lead toward development p300/CBP-targeted therapy.
Language: Английский
Citations
14
Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(9), P. 7283 - 7300
Published: April 27, 2024
The epidermal growth factor receptor (EGFR) tertiary C797S mutation is an important cause of resistance to Osimertinib, which seriously hinders the clinical application Osimertinib. Developing proteolysis-targeting chimeras (PROTACs) targeting EGFR mutants can offer a promising strategy overcome drug resistance. In this study, some novel PROTACs were designed and synthesized based on new inhibitor displayed potent degradation effect in H1975-TM cells harboring EGFRL858R/T790M/C797S. representative compound C6 exhibited DC50 10.2 nM against EGFRL858R/T790M/C797S IC50 10.3 H1975-TM. Furthermore, also showed activity various main mutants, including EGFRDel19/T790M/C797S. Mechanistic studies revealed that protein was achieved through ubiquitin–proteasome system. Finally, inhibited tumor xenograft model effectively safely. This study identifies PROTAC Osimertinib mediated by mutation.
Language: Английский
Citations
12
Advanced Science, Journal Year: 2024, Volume and Issue: 11(26)
Published: April 30, 2024
Abstract Proteolysis targeting chimeras (PROTACs) have emerged as a promising strategy for drug discovery and exploring protein functions, offering revolutionary therapeutic modality. Currently, the predominant approach to PROTACs mainly relies on an empirical design–synthesis–evaluation process involving numerous cycles of labor‐intensive synthesis‐purification bioassay data collection. Therefore, development innovative methods expedite PROTAC synthesis exploration chemical space remains highly desired. Here, direct‐to‐biology is reported streamline libraries plates, enabling seamless transfer reaction products cell‐based bioassays without need additional purification. By integrating amide coupling light‐induced primary amines o‐nitrobenzyl alcohols cyclization (PANAC) photoclick chemistry into plate‐based synthetic process, this produces with high efficiency structural diversity. Moreover, by employing platform screening, we smoothly found potent effectively inhibit triple‐negative breast cancer (TNBC) cell growth induce rapid, selective targeted degradation cyclin‐dependent kinase 9 (CDK9). The study introduces versatile assembling followed direct biological evaluation. This provides opportunity high‐throughput libraries, thereby enhancing accelerating PROTACs.
Language: Английский
Citations
11
Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown
Published: March 25, 2025
Language: Английский
Citations
1