Proteolysis targeting chimeras (PROTACs) in oncology: a review of patents and regulatory considerations

Abstract

Introduction: Proteolysis Targeting Chimeras (PROTACs) represents a groundbreaking advancement in drug discovery and targeted protein degradation. Unlike traditional small-molecule inhibitors, PROTACs leverage the cell's natural protein degradation machinery to selectively degrade pathogenic proteins, offering significant therapeutic potential for previously undruggable targets and complex diseases such as cancer and neurodegenerative disorders. Understanding the regulatory landscape governing their approval is crucial as their development accelerates.

Areas covered: This review provides an overview of recent patents, regulatory considerations, emerging concerns, and future perspectives of PROTACs in cancer management.

Expert opinion: From a regulatory perspective, PROTACs present unique challenges and opportunities. Their dual-functional nature requires a nuanced approach to classification and approval, blending small-molecule and biologic regulatory frameworks. Specific guidelines addressing pharmacokinetic and pharmacodynamic profiles are needed. Comprehensive preclinical evaluation and robust clinical trial designs are essential to manage off-target effects and immunogenic responses. The collaboration between regulatory bodies, academia, and industry is crucial for establishing a clear pathway for PROTAC approval. Future considerations must account for advancements in PROTAC technology to ensure safe and effective therapies reach patients. While PROTACs hold immense promise, their regulatory journey requires tailored guidelines and rigorous evaluation to realize their full potential.

Keywords: Cancer; PROTACs; emerging strategies; progress; recent patents; regulatory considerations; targeted protein degradation; ubiquitin-proteasome system.

Figure 1.

Mechanism of action PROTAC illustrates PROTAC-mediated targeted protein degradation via the ubiquitin-proteasome system by recruiting E3 ligases for ubiquitination.

Figure 2.

Fishbone diagrammatic representation illustrates the relationship between critical material attributes (CMAs) and critical process parameters (CPPs) in determining peptide drug product quality. Key factors include peptide synthesis, formulation, container closure system, and storage conditions.