Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Pharmacology

Background:

• Proteolysis targeting chimeras (PROTACs) represent a groundbreaking drug discovery paradigm.
• PROTACs leverage the cell's ubiquitin-proteasome system for targeted protein degradation.
• They offer a novel mechanism for modulating protein function beyond traditional inhibition.

Purpose of the Study:

• To summarize recent advancements in PROTAC technology over the past year.
• To highlight the diverse range of proteins targeted by PROTACs.
• To discuss the advantages and future challenges of PROTAC-based therapeutics.

Main Methods:

• Review of recent scientific literature on PROTACs.
• Analysis of PROTACs targeting various proteins of interest (POIs).
• Examination of clinical trial progress, including ARV-110 for prostate cancer.

Main Results:

• PROTAC technology has shown significant progress in targeting a wide array of proteins.
• The first orally available small molecule PROTAC, ARV-110, targeting the Androgen Receptor (AR), has entered Phase I clinical trials for metastatic castration-resistant prostate cancer.
• PROTACs demonstrate broad applicability as biological tools and potential therapeutic agents.

Conclusions:

• PROTACs are a rapidly advancing field with substantial potential for clinical applications.
• The development of ARV-110 marks a significant milestone in translating PROTAC technology to human trials.
• Continued research is essential to overcome challenges and fully realize the therapeutic promise of PROTACs.