Induced protein degradation: an emerging drug discovery paradigm
Ashton C. Lai,Craig M. Crews +1 more
TLDR
Induced protein degradation has the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.Abstract:
Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function, and this approach typically precludes targeting proteins that lack such amenable sites. Furthermore, high systemic drug exposures may be needed to maintain sufficient target inhibition in vivo, increasing the risk of undesirable off-target effects. Induced protein degradation is an alternative approach that is event-driven: upon drug binding, the target protein is tagged for elimination. Emerging technologies based on proteolysis-targeting chimaeras (PROTACs) that exploit cellular quality control machinery to selectively degrade target proteins are attracting considerable attention in the pharmaceutical industry owing to the advantages they could offer over traditional small-molecule strategies. These advantages include the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.read more
Citations
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Journal ArticleDOI
PROTACs: Current Trends in Protein Degradation by Proteolysis-Targeting Chimeras
TL;DR: This review looks at the history of degraders, followed by a section on the ubiquitin proteasome system (UPS) and E3 ligases used in PROTAC development, and discusses methodologies and strategies to surmount the challenges faced by these molecules.
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Design, synthesis, and biological evaluation of novel ubiquitin-activating enzyme inhibitors.
Yukihiro Itoh,Miki Suzuki +1 more
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Discovery of Thieno[2,3-e]indazole Derivatives as Novel Oral Selective Estrogen Receptor Degraders with Highly Improved Antitumor Effect and Favorable Druggability.
TL;DR: In general, compound 40 showed much better pharmacological profiles than the lead LSZ102, exhibiting growth inhibition of wild-type or tamoxifen-resistant MCF-7 cells, potent ERα degradation, together with superior pharmacokinetic properties, directional target tissue distribution including the brain, and robust antitumor efficacy in the mice breast cancer xenograft model.
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Exploring DCAF15 for reprogrammable targeted protein degradation
Coomar S,Dennis Gillingham +1 more
TL;DR: The arylsulfonamide is identified as the E3 ligase most amenable to chemical modifications and demonstrated its behaviour in bifunctional reprogramming.
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Characterization of cereblon-dependent targeted protein degrader by visualizing the spatiotemporal ternary complex formation in cells
TL;DR: It is demonstrated that BRD4-targeting and FKBP12 F36V -targeting degraders formed ternary complexes mainly in the nucleus and cytoplasm, suggesting that TPD molecules utilize the proteasome to degrade target proteins in their corresponding localized region.
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