Details

Autor(en) / Beteiligte

• Chirnomas, Deborah
• Hornberger, Keith R.
• Crews, Craig M.

Titel

Protein degraders enter the clinic — a new approach to cancer therapy

Ist Teil von

• Nature reviews. Clinical oncology, 2023-04, Vol.20 (4), p.265-278

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. Protein degraders constitute a new class of agents that eliminate, rather than just inhibit, their target proteins. These novel agents have recently entered testing in oncology trials, with initial data providing clinical proof of concept for the mechanism of action as well as the antitumour activity of heterobifunctional protein degraders. In this Review, the authors outline the progress in the development of such protein degraders for the treatment of cancer and consider prospects and potential challenges for these agents. Key points The concept of harnessing the natural, intracellular protein-degradation machinery (that is, the ubiquitin–proteasome system) to eliminate disease-causing proteins was proposed more than two decades ago. Since then, numerous primary papers and review articles have described the mechanistic development of protein degraders and their potential as a new therapeutic approach, including for patients with cancer. As of 8 January 2023, 18 heterobifunctional protein degraders are under evaluation in clinical trials in patients with various solid tumours and haematological cancers, and the first clinical data on these molecules are now emerging. Preclinical data that have been disclosed for the protein degraders currently in clinical development support their target specificity and their potency in inhibiting tumour growth compared with small-molecule inhibitors. Preliminary data for protein degraders that target the androgen receptor, the oestrogen receptor and BTK have shown encouraging clinical activity in patients with prostate cancer, breast cancer and chronic lymphocytic leukaemia, respectively, and results from additional ongoing clinical studies are anticipated.