Design, synthesis, and biological evaluation of first-in-class indomethacin-based PROTACs degrading SARS-CoV-2 main protease and with broad-spectrum antiviral activity DOI Creative Commons
Jenny Desantis,

Alessandro Bazzacco,

Michela Eleuteri

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 268, P. 116202 - 116202

Published: Feb. 6, 2024

To date, Proteolysis Targeting Chimera (PROTAC) technology has been successfully applied to mediate proteasomal-induced degradation of several pharmaceutical targets mainly related oncology, immune disorders, and neurodegenerative diseases. On the other hand, its exploitation in field antiviral drug discovery is still infancy. Recently, we described two indomethacin (INM)-based PROTACs displaying broad-spectrum activity against coronaviruses. Here, report design, synthesis, characterization a novel series INM-based that recruit either Von-Hippel Lindau (VHL) or cereblon (CRBN) E3 ligases. The panel was also enlarged by varying linker moiety. resulted very susceptible this modification, particularly for hijacking VHL as ligase, with one piperazine-based compound (PROTAC 6) showing potent anti-SARS-CoV-2 infected human lung cells. Interestingly, assays both uninfected virus-infected cells most promising emerged so far (PROTACs 5 demonstrated INM-PROTACs do not degrade PGES-2 protein, initially hypothesized, but induce concentration-dependent SARS-CoV-2 main protease (Mpro) Mpro-transfected SARS-CoV-2-infected Importantly, thanks target degradation, exhibited considerable enhancement respect indomethacin, EC50 values low-micromolar/nanomolar range. Finally, kinetic solubility well metabolic chemical stability were measured 6. Altogether, identification first class Mpro degraders demonstrating represents significant advance development effective, anti-coronavirus strategies.

Language: Английский

New-generation advanced PROTACs as potential therapeutic agents in cancer therapy DOI Creative Commons
Chao Wang, Yujing Zhang,

Wujun Chen

et al.

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

29
Targeting the undruggables—the power of protein degraders DOI Creative Commons
Chao Zhang, Yongbo Liu, Guangchen Li

et al.

Science Bulletin, Journal Year: 2024, Volume and Issue: 69(11), P. 1776 - 1797

Published: March 29, 2024

Undruggable targets typically refer to a class of therapeutic that are difficult target through conventional methods or have not yet been targeted, but great clinical significance. According statistics, over 80% disease-related pathogenic proteins cannot be targeted by current treatment methods. In recent years, with the advancement basic research and new technologies, development various technologies mechanisms has brought perspectives overcome challenging drug targets. Among them, protein degradation technology is breakthrough strategy for This can specifically identify directly degrade utilizing inherent pathways within cells. form includes types such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting Chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting (AUTAC), (AUTOTAC), degrader-antibody conjugate (DAC). article systematically summarizes application in degraders Finally, looks forward future direction prospects technology.

Language: Английский

Citations

18
Second-generation anti-amyloid monoclonal antibodies for Alzheimer’s disease: current landscape and future perspectives DOI Creative Commons

Byeong‐Hyeon Kim,

Sujin Kim, Yunkwon Nam

et al.

Translational Neurodegeneration, Journal Year: 2025, Volume and Issue: 14(1)

Published: Jan. 27, 2025

Abstract Alzheimer’s disease (AD) is the most common type of dementia. Monoclonal antibodies (MABs) serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors, such amyloid-β (Aβ) peptide, tau protein, and neuroinflammation. Specifically, based on their efficacy in removing Aβ plaques from brains patients with AD, U.S. Food Drug Administration has approved three anti-amyloid MABs, aducanumab (Aduhelm®), lecanemab (Leqembi®), donanemab (Kisunla™). Notably, received traditional approval after demonstrating clinical benefit, supporting cascade hypothesis. These MABs are categorized affinity to diverse conformational features Aβ, including monomer, fibril, protofibril, plaque forms well pyroglutamate Aβ. First-generation non-toxic monomeric solanezumab, bapineuzumab, crenezumab, failed demonstrate benefit trials. In contrast, second-generation aducanumab, lecanemab, donanemab, gantenerumab directed against species aggregates have shown that reducing deposition can be an effective strategy slow cognitive impairment AD. this review, we provide comprehensive overview current status, mechanisms, outcomes, limitations treatment Moreover, discuss perspectives future directions

Language: Английский

Citations

4
Discovery of E3 Ligase Ligands for Target Protein Degradation DOI Creative Commons
Jaeseok Lee, Young‐Jun Lee, Young Mee Jung

et al.

Molecules, Journal Year: 2022, Volume and Issue: 27(19), P. 6515 - 6515

Published: Oct. 2, 2022

Target protein degradation has emerged as a promising strategy for the discovery of novel therapeutics during last decade. Proteolysis-targeting chimera (PROTAC) harnesses cellular ubiquitin-dependent proteolysis system efficient interest. PROTAC consists target ligand and an E3 ligase so that it enables owing to induced proximity with ubiquitin ligases. Although great number PROTACs been developed far using previously reported ligands proteins their degradation, have mostly limited either CRBN or VHL ligands. Those showed limitation due cell type specific expression ligases recently resistance toward To overcome these hurdles, various spotlighted improve current technology. This review focuses on currently application in development PROTACs.

Language: Английский

Citations

69
Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors DOI Open Access
Gabriel LaPlante, Wei Zhang

Cancers, Journal Year: 2021, Volume and Issue: 13(12), P. 3079 - 3079

Published: June 20, 2021

The ubiquitin-proteasome system (UPS) is a critical regulator of cellular protein levels and activity. It is, therefore, not surprising that its dysregulation implicated in numerous human diseases, including many types cancer. Moreover, since cancer cells exhibit increased rates turnover, their heightened dependence on the UPS makes it an attractive target for inhibition via targeted therapeutics. Indeed, clinical application proteasome inhibitors treatment multiple myeloma has been very successful, stimulating development small-molecule targeting other components. On hand, while discovery potent selective chemical compounds can be both challenging time consuming, area degradation through utilization machinery seen promising developments recent years. repertoire proteolysis-targeting chimeras (PROTACs), which employ E3 ligases cancer-related proteins proteasome, continues to grow. In this review, we will provide thorough overview highlight advancements strategies

Language: Английский

Citations

57
Discovery of Potent PROTACs Targeting EGFR Mutants through the Optimization of Covalent EGFR Ligands DOI
Hongyi Zhao, Haipeng Wang, Yu-Ze Mao

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(6), P. 4709 - 4726

Published: March 7, 2022

Drug resistance caused by epidermal growth factor receptor (EGFR) mutation has largely limited the clinical use of EGFR tyrosine kinase inhibitors (EGFR-TKIs) for treatment non-small-cell lung cancer (NSCLC). Herein, to overcome intractable problem drug resistance, proteolysis targeting chimeras (PROTACs) mutants were developed optimizing covalent ligands. Covalent or reversible pyrimidine- purine-containing PROTACs designed, synthesized, and evaluated. As a consequence, PROTAC CP17, with novel ligand, was discovered as highly potent degrader against EGFRL858R/T790M EGFRdel19, reaching lowest DC50 values among all reported EGFR-targeting PROTACs. Furthermore, CP17 exhibited excellent cellular activity H1975 HCC827 cell lines high selectivity. Mechanism investigation indicated that lysosome involved in degradation process. Importantly, binding strategy proven be an effective approach design EGFRL858R/T790M, which laid practical foundation further development

Language: Английский

Citations

51
Recent Advances in PROTACs for Drug Targeted Protein Research DOI Open Access
Tingting Yao, Heng Xiao, Hong Wang

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(18), P. 10328 - 10328

Published: Sept. 7, 2022

Proteolysis-targeting chimera (PROTAC) is a heterobifunctional molecule. Typically, PROTAC consists of two terminals which are the ligand protein interest (POI) and specific E3 ubiquitin ligase, respectively, via suitable linker. degradation target performed through ubiquitin-proteasome system (UPS). The general process that binds to ligase form ternary complex label with ubiquitination. ubiquitinated recognized degraded by proteasome in cell. At present, PROTAC, as new type drug, has been developed degrade variety cancer proteins other disease proteins, shown good curative effects on diseases. For example, PROTACs targeting AR, BR, BTK, Tau, IRAK4, have unprecedented clinical efficacy cancers, neurodegenerative diseases, inflammations, fields. Recently, entered phase rapid development, opening field for biomedical research development. This paper reviews various fields targeted recent years summarizes prospects hot targets indications PROTAC.

Language: Английский

Citations

43
The importance of cellular degradation kinetics for understanding mechanisms in targeted protein degradation DOI Creative Commons
Kristin M. Riching, Elizabeth A. Caine, Marjeta Urh

et al.

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(14), P. 6210 - 6221

Published: Jan. 1, 2022

Targeted protein degradation is a dynamic process regulated not only by the kinetics and mechanisms of degrader compound, but also native homeostasis cellular regulation target protein. Image created with BioRender.com.

Language: Английский

Citations

38
Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks DOI Creative Commons
Ke Xu, Jie Ma, Sean R. R. Hall

et al.

Theranostics, Journal Year: 2023, Volume and Issue: 13(2), P. 704 - 723

Published: Jan. 1, 2023

The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances.Cancer often hijack this during initiation progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin likely to influence the genetic selection malignant transformation.Hyperactivation NRF2 confers multi-faceted role, recently, increasing evidence shows close interplay between metabolic reprogramming tumor immunity remodelling contributes its aggressiveness, treatment resistance (radio-/chemo-/immune-therapy) susceptibility metastases.Here, we discuss detail special immune fitness enabled by aberration NSCLC.Furthermore, summarize similarities differences dysregulated two major histo-subtypes NSCLC, provide mechanistic insights on poor response immunotherapy despite their high immunogenicity, outline evolving strategies treat recalcitrant subset.Finally, integrate bioinformatic analysis publicly available datasets illustrate new partners/effectors NRF2-addicted cells, which may into context-directed treatment.

Language: Английский

Citations

37
Targeting SLC transporters: small molecules as modulators and therapeutic opportunities DOI Creative Commons
Avner Schlessinger, Nicole Zatorski, Keino Hutchinson

et al.

Trends in Biochemical Sciences, Journal Year: 2023, Volume and Issue: 48(9), P. 801 - 814

Published: June 22, 2023

Language: Английский

Citations

34