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

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.

Fig. 1 │. Targeting proteins involved in cancer pathogenesis with protein degraders versus small-molecule inhibitors.

Protein degraders mediate a transient interaction between an E3 ligase and a target protein, leading to ubiquitin (Ub) tagging of the target protein and its subsequent degradation by the proteasome. Small-molecule inhibitors bind to an active site on a target protein to block its activity.

Fig. 2 │. Timeline of key advances in protein degrader development.

CRBN, cereblon; IMiD, immunomodulatory drug; PROTAC, PROteolysis TArgeting Chimera; VHL, Von Hippel-Lindau. ] Extraordinary progress has been made since the first publication on protein degrader technology in 2001, including design and refinement of the molecules through medicinal chemistry that ultimately led to initiation of clinical trials of protein degraders in patients with cancer.

Fig. 3 │. Clinical proof-of-concept for PROTAC protein degraders

a │ Immunohistochemistry images demonstrating decreased androgen receptor (AR) protein levels in a wild-type/amplified tumour from a patient with metastatic castration-resistant prostate cancer (mCRPC) following 6 weeks of 280 mg bavdegalutamide once daily. b │ CT images showing near complete reduction of retroperitoneal adenopathy in an AR T878A/H875Y-positive patient with mCRPC following four 28-day cycles of 140 mg bavdegalutamide once daily^–. c │ Quantitative immunofluorescence data demonstrating decreased oestrogen receptor (ER) protein levels in tumour biopsy samples from patients with breast cancer after a median of 31 days (range 16–77) of once-daily treatment with doses of ARV-471 used in phase 1 dose escalation. d │ CT images showing reduction in target lesions in a patient with breast cancer harbouring an ESR1 D538G mutation after four 28-day cycles of 120 mg ARV-471 once daily. AQUA, automated quantitative analysis; PROTAC, PROteolysis TArgeting Chimera