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Protein degraders enter the clinic - a new approach to cancer therapy. | LitMetric

Protein degraders enter the clinic - a new approach to cancer therapy.

Nat Rev Clin Oncol

Department of Molecular, Cellular & Developmental Biology, Yale University, New Haven, CT, USA.

Published: April 2023

AI Article Synopsis

  • * Unlike traditional small-molecule inhibitors, protein degraders enable lower drug concentrations, can target several protein copies, and may even tackle previously 'undruggable' proteins.
  • * As of 2023, 18 protein degraders are in clinical trials, with early data suggesting they have promising potential as cancer therapies, although more research is still needed.

Article Abstract

Heterobifunctional protein degraders, such as PROteolysis TArgeting Chimera (PROTAC) protein degraders, constitute a novel therapeutic modality that harnesses the cell's natural protein-degradation machinery - that is, the ubiquitin-proteasome system - to selectively target proteins involved in disease pathogenesis for elimination. Protein degraders have several potential advantages over small-molecule inhibitors that have traditionally been used for cancer treatment, including their event-driven (rather than occupancy-driven) pharmacology, which permits sub-stoichiometric drug concentrations for activity, their capacity to act iteratively and target multiple copies of a protein of interest, and their potential to target nonenzymatic proteins that were previously considered 'undruggable'. Following numerous innovations in protein degrader design and rigorous evaluation in preclinical models, protein degraders entered clinical testing in 2019. Currently, 18 protein degraders are in phase I or phase I/II clinical trials that involve patients with various tumour types, with a phase III trial of one initiated in 2022. The first safety, efficacy and pharmacokinetic data from these studies are now materializing and, although considerably more evidence is needed, protein degraders are showing promising activity as cancer therapies. Herein, we review advances in protein degrader development, the preclinical research that supported their entry into clinical studies, the available data for protein degraders in patients and future directions for this new class of drugs.

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41571-023-00736-3DOI Listing

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