Chemistries of bifunctional PROTAC degraders

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(16), P. 7066 - 7114

Published: Jan. 1, 2022

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

Language: Английский

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Small molecule inhibitors targeting the cancers

MedComm, Journal Year: 2022, Volume and Issue: 3(4)

Published: Oct. 13, 2022

Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary therapies for cancer. Due to their advantages a wide range targets, convenient medication, ability penetrate into central nervous system, many efforts have been devoted developing more small inhibitors. To date, 88 approved by United States Food Drug Administration treat cancers. Despite remarkable progress, cancer treatment still face obstacles, such as low response rate, short duration response, toxicity, biomarkers, resistance. better promote development targeting cancers, we comprehensively reviewed involved all agents pivotal drug candidates clinical trials arranged signaling pathways classification We discussed lessons learned from these agents, proper strategies overcome resistance arising different mechanisms, combination concerned Through our review, hoped provide insights perspectives research treatment.

Language: Английский

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Redox regulation: mechanisms, biology and therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 7, 2025

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both onset progression of various diseases. Under physiological conditions, oxidative free radicals generated by mitochondrial respiratory chain, endoplasmic reticulum, NADPH oxidases can be effectively neutralized NRF2-mediated antioxidant responses. These responses elevate synthesis superoxide dismutase (SOD), catalase, well key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption this finely tuned equilibrium is closely linked to pathogenesis wide range Recent advances have broadened our understanding molecular mechanisms underpinning dysregulation, highlighting pivotal roles genomic instability, epigenetic modifications, protein degradation, metabolic reprogramming. findings provide foundation for exploring regulation mechanistic basis improving therapeutic strategies. While antioxidant-based therapies shown early promise conditions where stress plays primary pathological role, efficacy diseases characterized complex, multifactorial etiologies remains controversial. A deeper, context-specific signaling, particularly redox-sensitive proteins, designing targeted aimed at re-establishing balance. Emerging small molecule inhibitors that target specific cysteine residues proteins demonstrated promising preclinical outcomes, setting stage forthcoming clinical trials. In review, we summarize current intricate relationship disease also discuss how these insights leveraged optimize strategies practice.

Language: Английский

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Formation of C(sp²)–C(sp³) Bonds Instead of Amide C–N Bonds from Carboxylic Acid and Amine Substrate Pools by Decarbonylative Cross-Electrophile Coupling

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(18), P. 9951 - 9958

Published: May 1, 2023

Carbon-heteroatom bonds, most often amide and ester are the standard method to link together two complex fragments because carboxylic acids, amines, alcohols ubiquitous reactions reliable. However, C-N C-O linkages a metabolic liability they prone hydrolysis. While C(sp

Language: Английский

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A beginner’s guide to current synthetic linker strategies towards VHL-recruiting PROTACs

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

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Protein degradation: expanding the toolbox to restrain cancer drug resistance

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Jan. 24, 2023

Abstract Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib proteolysis-targeting chimeric have been developed. Compared intervention at the transcriptional level, targeting process seems be more rapid direct strategy. Proteasomal proteolysis lysosomal are most critical quality control systems responsible for proteins or organelles. Although proteasomal inhibitors (e.g., chloroquine) achieved certain improvements some application scenarios, their routine practice is still long way off, which due lack precise capabilities inevitable side effects. In-depth studies regulatory mechanism regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), chaperones, expected provide clues developing reducing Here, we discuss underlying mechanisms regulating efflux, metabolism, DNA repair, target alteration, downstream bypass signaling, sustaining stemness, tumor microenvironment remodeling delineate functional roles resistance. We also highlight specific DUBs, discussing possible modulating cancer A systematic summary molecular basis by regulates will help facilitate development appropriate strategies.

Language: Английский

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Antiviral PROTACs: Opportunity borne with challenge

Cell Insight, Journal Year: 2023, Volume and Issue: 2(3), P. 100092 - 100092

Published: March 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.

Language: Английский

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Small-Molecule Ferritin Degrader as a Pyroptosis Inducer

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(17), P. 9815 - 9824

Published: April 24, 2023

Exploring the response of malignant cells to intracellular metabolic stress is critical for understanding pathologic processes and developing anticancer therapies. Herein, we developed ferritin-targeting proteolysis targeting chimeras (PROTACs) establish iron excess inside cancer investigated subsequent cellular behaviors. We conjugated oleic acid that binds ferritin dimer ligand von Hippel–Lindau (VHL) E3 ligase through an alkyl linker. The screened chimera, DeFer-2, degraded then rapidly elevated free content, thereby initiating caspase 3-GSDME-mediated pyroptosis in rather than typical ferroptosis always associated with ion overload. According its structural physicochemical characteristics, DeFer-2 was loaded into a tailored albumin-based nano-formulation, which substantially inhibited tumor growth prolonged survival time mice bearing B16F10 subcutaneous tumors negligible adverse effects. This study PROTAC overload stress, revealed dysregulation-mediated pyroptosis, provided PROTAC-based inducer treatment.

Language: Английский

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Development of Substituted Phenyl Dihydrouracil as the Novel Achiral Cereblon Ligands for Targeted Protein Degradation

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(4), P. 2904 - 2917

Published: Feb. 7, 2023

Glutarimides such as thalidomide, pomalidomide, and lenalidomide are the most frequently used ligands to recruit E3 ubiquitin ligase cereblon (CRBN) for development of proteolysis-targeting chimeras (PROTACs). Due rapid spontaneous racemization glutarimides, CRBN-recruiting PROTACs synthesized a mixture racemates or diastereomers. Since (S)-enantiomer is primarily responsible binding CRBN, existence largely inactive (R)-enantiomer complicates drug process. Herein, we report that substituted achiral phenyl dihydrouracil (PDHU) can be novel class CRBN PROTACs. Although parent PDHU has minimal affinity found some PDHUs had comparable lenalidomide. Structural modeling provided further understanding molecular interactions between CRBN. also have greater stability than Finally, potent BRD4 degraders were developed by employing trisubstituted PDHUs.

Language: Английский

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Current advances of small molecule E3 ligands for proteolysis-targeting chimeras design

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 256, P. 115444 - 115444

Published: May 8, 2023

Language: Английский

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