Novel approaches to targeted protein degradation technologies in drug discovery

ABSTRACT

Introduction

Target protein degradation (TPD) provides a novel therapeutic modality, other than inhibition, through the direct depletion of target proteins. Two primary human protein homeostasis mechanisms are exploited: the ubiquitin-proteasome system (UPS) and the lysosomal system. TPD technologies based on these two systems are progressing at an impressive pace.

Areas Covered

This review focuses on the TPD strategies based on UPS and lysosomal system, mainly classified into three types: Molecular Glue (MG), PROteolysis Targeting Chimera (PROTAC), and lysosome-mediated TPD. Starting with a brief background introduction of each strategy, exciting examples and perspectives on these novel approaches are provided.

Expert Opinion

MGs and PROTACs are two major UPS-based TPD strategies that have been extensively investigated in the past decade. Despite some clinical trials, several critical issues remain, among which is emphasized by the limitation of targets. Recently developed lysosomal system-based approaches provide alternative solutions for TPD beyond UPS’ capability. The newly emerging novel approaches may partially address issues that have long plagued researchers, such as low potency, poor cell permeability, on-/off-target toxicity, and delivery efficiency. Comprehensive considerations for the rational design of protein degraders and continuous efforts to seek effective solutions are imperative to advance these strategies into clinical medications.

KEYWORDS:

• Target Protein Degradation (TPD)
• protein degraders
• drug discovery
• AuTophagosome-TEthering Compound (ATTEC)
• AUtophagy-TArgeting Chimera (AUTAC)
• AUTOphagy-TArgeting Chimera (AUTOTAC)
• lysosomal system
• LYsosome-TArgeting Chimera (LYTAC)
• Molecular Glue (MG)
• PROteolysis Targeting Chimera (PROTAC)
• Ubiquitin-Proteasome System (UPS)

Article highlights

• Ubiquitin-proteasome system (UPS) and lysosomal system are two primary human protein homeostasis mechanisms widely exploited to achieve targeted protein degradation (TPD).

• Molecular Glue (MG) and PROteolysis Targeting Chimera (PROTAC) are two major strategies for UPS-based protein degradation, while lysosome-mediated TPD strategies include LYsosome-TArgeting Chimera (LYTAC), AUtophagy-TArgeting Chimera (AUTAC), AUTOphagy-TArgeting Chimera (AUTOTAC), and AuTophagosome-TEthering Compound (ATTEC).

• MGs were first discovered in plant hormones, and the largest class of current MGs in development and clinical trials are immunomodulatory imide drugs (IMiDs)-based.

• Most MGs are discovered serendipitously or from screening, but rational design approaches for novel MGs are emerging.

• The developmental trend of PROTACs is to achieve higher potency, lower on-/off-target toxicity, and more efficient delivery, with novel approaches highlighted by developing dual PROTACs, macrocyclic PROTACs, Pre-PROTACs, and Ab-PROTACs.

• Lysosome-mediated TPD technologies enable the degradation of extracellular proteins, aggregated proteins, damaged organelles, etc., significantly expanding the range of drug targets.

• Newly emerging PROTAC technologies such as theranostic PROTACs, DeUBiquitinase-TArgeting Chimeras (DUBTACs), and Regulated Induced Proximity TArgeting Chimeras (RIPTACs) may offer potential paradigm-shifting strategies.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was partially supported by a grant from the Cancer Prevention and Research Institute of Texas (CPRIT) (RP210062), and the John D. Stobo, M.D. Distinguished Chair Endowment Fund.