PROTACs in gastrointestinal cancers

Abstract

Proteolysis targeting chimera (PROTAC) presents a powerful strategy for targeted protein degradation (TPD). The heterobifunctional PROTAC molecule consists of an E3 ligase ligand covalently linked to a protein of interest (POI) via a linker. PROTAC can induce ubiquitinated proteasomal degradation of proteins by hijacking the ubiquitin-proteasome degradation system (UPS). This technique has the advantages of broad targeting profile, good cell permeability, tissue specificity, high selectivity, oral bioavailability, and controllability. To date, a growing number of PROTACs targeting gastrointestinal cancers have been successfully developed, and, in many cases, their POIs have been validated as clinical drug targets. To the best of our knowledge, 15 PROTACs against various targets are currently tested in clinical trials, and many more are likely to be added in the near future. Therefore, this paper details the mechanism, research progress, and application in clinical trials of PROTACs, and summarizes the research achievements related to PROTACs in gastrointestinal cancers. Finally, we discuss the advantages and potential challenges of PROTAC for cancer treatment.

Keywords: E3 ligases; PROTACs; cancer treatment; gastrointestinal cancers; targeted protein degradation.

Graphical abstract

Figure 1

Protein degradation mechanism of PROTAC E1-activating enzyme activates ubiquitin and transfers it to E2-binding enzyme. Then, upon PROTAC entries into the cell, the POI ligand binds specifically to the corresponding POI, while the other ligand combines with the E3 ligase. Thereby, a POI-PROTAC-E3 ligase ternary complex is formed. E3 ligase then mediates the ubiquitination of POI through E2-binding enzymes. Ultimately, the ubiquitin-labeled POI is specifically identified and selectively degraded through the proteasome and the ternary complex disintegrates.^,,

Figure 2

The main events and milestones in the development of the PROTAC technique

Figure 3

Chemical structure of third-generation PROTACs

Figure 4

Spatiotemporal-manner-controlled PROTACs (A) Phospho-dependent PROTAC. Active PROTAC can form a ternary complex with E3 ligase and POI, which mediates the ubiquitination and degradation of POI. (B) Photoswitchable PROTAC achieves interconversion between inactive and active PROTAC conformers through reversible optical control. Ultimately, reversible and spatiotemporal-manner-controlled protein degradation is achieved.^, (C) Photocaged PROTAC removes the caging group by irreversible optical control, which ultimately leads to photoinduced protein degradation.^,,,,

Figure 5

Application of PROTACs in pancreatic cancer PROTACs ubiquitinate and degrade POIs, which in turn affects the downstream signaling pathways or targets of POIs, ultimately inhibiting the progression of pancreatic cancer.^,,,,,,,,,,

Figure 6

Chemical structure of PROTACs applied to gastrointestinal cancer