Emerging New Concepts of Degrader Technologies

Abstract

Traditional drug discovery focuses on identifying direct inhibitors of target proteins. This typically relies on a measurable biochemical readout and accessible binding sites whose occupancy influences the function of the target protein. These requirements preclude many disease-causing proteins from being 'druggable' targets, and these proteins are categorized as 'undruggable'. The proteolysis-targeting chimera (PROTAC) technology provides powerful tools to degrade these undruggable targets and has become a promising approach for drug discovery. However, the PROTAC technology has some limitations, and emerging new degrader technologies may greatly broaden the spectrum of targets that could be selectively degraded by harnessing a second major degradation pathway in cells. We review key emerging technologies that exploit the lysosomal degradation pathway and discuss their potential applications and limitations.

Keywords: ATTEC; AUTAC; LYTAC; PROTAC; protein degradation; undruggable targets.

Figure 1

Schematic Models of Established Strategies to Selectively Target a Protein of Interest (POI). (A) Schematic illustration of DNA- and RNA-targeting technologies such as genome editing (represented by a pair of scissors cutting the target DNA) or antisense oligonucleotides (ASOs) that induce the target RNA degradation and protein translation inhibition. (B) Schematic illustration of the hydrophobic tagging (HyT) technology, which adds a hydrophobic tag onto POIs to induce their degradation via the proteasome, independently of E3 ligases and ubiquitination. (C) Schematic illustration of the four major PROTAC systems utilizing the indicated E3 ligase subunits. The PROTAC molecules bring the POIs in proximity to the corresponding E3 ligases to facilitate POI K48 polyubiquitination (Ub), leading to their subsequent degradation via the proteasome. All molecules were drawn based on public PDB files: CRBN-PROTAC-BRD4 (PDB: 6BN7); VHL-PROTAC-BRD4 (PDB: 5T35); cIAP1 (PDB: 3UW4), CRABP2 (PDB: 3CBS); MDM2 (PDB: 4HF2), AR (PDB: 1XOW); Ub (PDB: 5GOI); HyT POI DHFR (PDB: 5UII); proteasome (PDB: 4CR2). The PDB files of the cIAP and MDM2 PROTAC complexes were unavailable, and their PROTAC molecules therefore are represented by cartoon shapes.

Figure 2

Key Figure. Schematic Models of Emerging Degrader Technologies. (A) LYTACs utilize a glycan tag to mark an extracellular protein of interest (POI) for intracellular lysosomal degradation following receptor-mediated internalization. Note that the LYTAC paper has not yet been peer reviewed and formally published. (B) AUTACs bind to the POI and add a degradation tag mimicking S-guanylation, a post-translational modification that triggers K63 polyubiquitination (Ub) of the POI. The POI is then recognized by the autophagy receptor SQSTM1/p62 and is recruited to the selective autophagy pathway for degradation. For the AUTAC molecule, the G pentagon represents the chemical moiety mimicking S-guanylation and the linked pacman shape represents the targeting recognition moiety. (C) ATTECs interact with both the POI and LC3, tethering the POI to the phagophores or autophagosomes for subsequent autophagic degradation.