Beyond canonical PROTAC: biological targeted protein degradation (bioTPD)

Abstract

Targeted protein degradation (TPD) is an emerging therapeutic strategy with the potential to modulate disease-associated proteins that have previously been considered undruggable, by employing the host destruction machinery. The exploration and discovery of cellular degradation pathways, including but not limited to proteasomes and lysosome pathways as well as their degraders, is an area of active research. Since the concept of proteolysis-targeting chimeras (PROTACs) was introduced in 2001, the paradigm of TPD has been greatly expanded and moved from academia to industry for clinical translation, with small-molecule TPD being particularly represented. As an indispensable part of TPD, biological TPD (bioTPD) technologies including peptide-, fusion protein-, antibody-, nucleic acid-based bioTPD and others have also emerged and undergone significant advancement in recent years, demonstrating unique and promising activities beyond those of conventional small-molecule TPD. In this review, we provide an overview of recent advances in bioTPD technologies, summarize their compositional features and potential applications, and briefly discuss their drawbacks. Moreover, we present some strategies to improve the delivery efficacy of bioTPD, addressing their challenges in further clinical development.

Expanding the horizons of targeted protein degradation: A non-small molecule perspective

“…In contradistinction, small-molecule PROTACs offer enhanced absorptive capacity and improved drug formulation attributes, thereby propelling the gradual ascendancy of small-molecule variants to the forefront 26 . Nevertheless, certain limitations persist, notably suboptimal physicochemical properties culminating in diminished cellular permeability and subpar metabolic performance 27 , 28 . Over the past decade, the landscape of targeted protein degradation has been revolutionized by the rapid proliferation of macromolecular PROTACs, facilitated by advancements in structural biology, click chemistry and coupling methodologies.…”

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

“…We summarize the clinically tested PROTACs and molecular glue degraders targeting RTKs in Table 3. The latest protein degradation strategies also include lysosometargeting chimeras (LYTACs), such as endosome-lysosome and autophagy-lysosome, and new degradation methods like dTAG, hydrophobic tagging, and Trim-Away [144][145][146].…”

Degron-based bioPROTACs for controlling signaling in CAR T cells

“…For the majority of bioPROTACs, truncated endogenous E3 ligases have been utilized to promote ubiquitination of a POI 28 . Interestingly, degrons, short degradation inducing sequences, can replace these much bulkier protein domains while retaining degradation activity 18,29 . Degrons known to interact with E3 ligases have been screened for development of bioPROTACs that target the tau protein 26,27 .…”