Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods

Journal of Chemical Information and Modeling, Journal Year: 2023, Volume and Issue: 63(17), P. 5408 - 5432

Published: Aug. 21, 2023

The therapeutic approach of targeted protein degradation (TPD) is gaining momentum due to its potentially superior effects compared with inhibition. Recent advancements in the biotech and pharmaceutical sectors have led development compounds that are currently human trials, some showing promising clinical results. However, use computational tools TPD still limited, as it has distinct characteristics traditional drug design methods. involves creating a ternary structure (protein-degrader-ligase) responsible for biological function, such ubiquitination subsequent proteasomal degradation, which depends on spatial orientation interest (POI) relative E2-loaded ubiquitin. Modeling this necessitates unique blend initially developed small molecules (e.g., docking) biologics protein-protein interaction modeling). Additionally, degrader molecules, particularly heterobifunctional degraders, generally larger than conventional molecule drugs, leading challenges determining drug-like properties like solubility permeability. Furthermore, catalytic nature makes occupancy-based modeling insufficient. consists multiple interconnected yet steps, POI binding, E3 ligase interactions, ubiquitination, along properties. A comprehensive set needed address dynamic induced proximity complex implications ubiquitination. In Perspective, we discuss current state TPD. We start by describing series steps involved process experimental methods used characterize them. Then, delve into detailed analysis employed also present an integrative proven successful impact project decisions. Finally, examine future prospects areas greatest potential impact.

Language: Английский

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Recent advances in targeted protein degraders as potential therapeutic agents

Molecular Diversity, Journal Year: 2023, Volume and Issue: 28(1), P. 309 - 333

Published: Feb. 15, 2023

Language: Английский

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Insight into Recent Advances in Degrading Androgen Receptor for Castration-Resistant Prostate Cancer

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

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Confounding Factors in Targeted Degradation of Short-Lived Proteins

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(7), P. 1484 - 1494

Published: July 3, 2024

Targeted protein degradation has recently emerged as a novel option in drug discovery. Natural half-life is expected to affect the efficacy of degrading agents, but what extent it influences target not been systematically explored. Using simple mathematical modeling degradation, we find that natural dramatic effect on level induced by degrader agent which can pose significant hurdles screening efforts. Moreover, show upon for degraders short-lived proteins, agents stall synthesis, such GSPT1 and generally cytotoxic compounds, deceptively appear protein-degrading agents. This exemplified disappearance proteins MCL1 MDM2 treatment with doxorubicin. These findings have implications selection well type control experiments required conclude works bona fide targeted degrader.

Language: Английский

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

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

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