Clinical Translation of Targeted Protein Degraders

Abstract

Targeted protein degradation (TPD) has emerged as a potentially transformational therapeutic modality with considerable promise. Molecular glue degraders remodel the surface of E3 ligases inducing interactions with neosubstrates resulting in their polyubiquitination and proteasomal degradation. Molecular glues are clinically precedented and have demonstrated the ability to degrade proteins‐of‐interest (POIs) previously deemed undruggable due to the absence of a traditional small molecule binding pocket. Heterobifunctional proteolysis targeting chimeras (PROTACs) possess ligands for an E3 complex and the POIs, which are chemically linked together, and similarly hijack the ubiquitin machinery to deplete the target. There has been a recent surge in the number of degraders entering clinical trials, particularly directed toward cancer. Nearly all utilize CRL4CRBN as the E3 ligase, and a relatively limited diversity of POIs are currently targeted. In this review, we provide an overview of the degraders in clinical trials and provide a perspective on the lessons learned from their development and emerging human data that will be broadly useful to those working in the TPD field.

Targeted protein degradation in CNS disorders: a promising route to novel therapeutics?

“…Two key E3 ligases have been routinely harnessed for TPD approaches. CRBN ligands dominate PROTACs and MG in clinical stages ( Kong and Jones, 2023 ), mainly due to their size and “drug-like” properties, although the risk of teratogenicity remains a concern ( Smith and Mitchell, 2018 ). Two VHL-based PROTACs, namely BCL-X L degrader DT2216 ( Khan et al, 2019 ) and KRAS G12D degrader ASP-3082 ( Nagashima et al, 2022 ) are in clinical trials, and E7820, which glues RBM39 to the DCAF15 ligase complex ( Chirnomas et al, 2023 ; Kong and Jones, 2023 ).…”

“…PROTAC (proteolysis-targeting chimera) or molecular glue (MG)-driven ternary complex formation with an E3 ligase utilizes cells’ ubiquitin-proteasome system (UPS) to degrade targets. Several such molecules have entered clinical development ( Kong and Jones, 2023 ). Two E3 ligases, Von Hippel–Lindau (VHL) and Cereblon (CRBN), are regularly harnessed for therapeutic TPD approaches; both belong to the Cullin-RING E3 Ligase (CRL) family ( Bondeson et al, 2015 ; Zengerle et al, 2015 ).…”

Novel Therapeutic Modalities: The Future is Now

“…However, to date, limited information and guidance has been made available with regard to the clinical pharmacology aspects of TPDs. In their State‐of‐the‐Art contribution entitled “Clinical Translation of Targeted Protein Degraders,” 22 Kong and Jones from the Dana‐Farber Cancer Institute provide an overview of TPDs in clinical trials and a perspective on the lessons learned from their development and emerging human data. This may provide a useful source for clinical pharmacologists working in this rapidly growing field, specifically with regard to PK‐pharmacodynamic (PK‐PD) profiling, the use of biomarkers, safety, and the emergence of the new class of E3 ligases to overcome the reliance on hijacked E3 ligase that may cause drug resistance.…”

Discovery of Alkenyl Oxindole as a Novel PROTAC Moiety for Targeted Protein Degradation via CRL4DCAF11Recruitment

“…It has been successfully applied to degrade more than 100 target proteins, including those previously considered "undruggable" 12 . Moreover, more than 20 PROTACs are currently undergoing clinical trials since 2019 [13][14][15][16] , indicating that PROTAC technology is a promising therapeutic strategy.…”