Small-Molecule PROTACs for Cancer Immunotherapy

Abstract

Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.

Keywords: proteolysis targeting chimera; small molecule inhibitors; targeted protein degradation; tumor immunotherapy; tumor microenvironment.

Figure 1

Schematic illustration of the mechanism of PROTAC. Firstly, the PROTAC molecule binds with POI and E3 ligase using the functional groups in its two ends. Then, the PROTAC molecule joins these two proteins together, forming a complex consisting of POI, PROTAC, and E3 ligase. The proximity of POI to the E3 ligase enables the ubiquitination of POI. Subsequently, the ubiquitin-tagged protein is recognized and degraded by the proteasome, and the PROTAC molecule can be reused to connect the next POI and E3 ligase.

Figure 2

The chemical structures of representative PROTACs targeting the PD-1/PD-L1 checkpoint signal axis. (A) The chemical structures of representative PROTACs targeting PD-L1 protein. (B) The chemical structures of representative PROTACs targeting SHP-2. (C) The chemical structures of representative PROTACs targeting BET. DC₅₀—half-maximal degradation concentration; IC₅₀—half-maximal inhibition concentration.

Figure 3

The chemical structures of representative PROTACs targeting IDO1. (A) The chemical structure of the first PROTAC targeting IDO1. (B) The chemical structure of IDO-targeting PROTAC peptide. DC₅₀—half-maximal degradation concentration; Dmax—maximum degradation; IC₅₀—half-maximal inhibition concentration.

Figure 4

The chemical structures of representative PROTACs targeting HDAC. DC₅₀—half-maximal degradation concentration; Dmax—maximum degradation; IC₅₀—half-maximal inhibition concentration.

Figure 5

The chemical structures of representative PROTACs target the Bcl-2 family. DC₅₀—half-maximal degradation concentration; Dmax—maximum degradation; IC₅₀—half-maximal inhibition concentration.

Figure 6

The chemical structure of the first PROTAC targeting STAT3. DC₅₀—half-maximal degradation concentration; IC₅₀—half-maximal inhibition concentration.

Figure 7

The chemical structures of representative PROTACs targeting MAPK. DC₅₀—half-maximal degradation concentration; Dmax—maximum degradation; IC₅₀—half-maximal inhibition concentration.

Figure 8

The chemical structure of representative PROTACs targeting COX-1/2, NAMPT, and TGF-β1. (A) The chemical structure of COX-1/2 targeting PROTAC moiety in nanomedicine. (B) The chemical structure of representative PROTACs targeting NAMPT. (C) The chemical structure of representative PROTACs targeting TGF-β1. IC₅₀—half-maximal inhibition concentration.