Proteolysis targeting chimera (PROTAC) is a bifunctional small molecule. Interestingly, dual PROPACs are dual-targeted degradation molecules that combine the concepts of PROTAC and dual-targeting. Dual PROPACs degrade two completely different pathway targets while simultaneously taking advantage of both PROTAC and dual-target drugs. Thus, dual PROPACs not only achieve the similar effect with the double antibody, but also maintain the advantages of small molecule drugs.

For example, dual PROTACs consist of an E3 ligand (CRBN or VHL ligand) linking two inhibitors of completely different types of targets. They enable a single small molecule to degrade two completely different targets simultaneously in tumor cells.

In this article, we will introduce a CRBN-Based dual PROTAC for EGFR and PARP, DP-C-4.

To one’s excitement, DP-C-4 is the first successful example of dual PROTACs. Specifically, dual PROTACs make up of gefitinib, olaparib, and CRBN or VHL E3 ligands. DP-C-4 successfully degrades both the epidermal growth factor receptor (EGFR) and poly(ADP-ribose) polymerase (PARP) simultaneously in cancer cells. A research found that DP-C-4 has degradation effects on EGFR and PARP simultaneously in a dose-dependent manner in SW1990 cells. There is no doubt that, DP-C-4 creatively uses biocompatible amino acids as the linkage framework, and rapidly realizes the synthesis of double-targeted trisomy compounds. DP-C-4 greatly expands the application of PROTAC technology and opening up a whole new field of drug discovery.

In conclusion, DP-C-4 is a CRBN-Based dual PROTAC for EGFR and PARP could provide an effective study for cancer diseases.


[1]. Zheng M, et al. J Med Chem. 2021 Jun;64(11):7839-7852.