Natural Compound‐Rhein and PROTACs Unleash Potent VEGFR‐2 Degraders

Abstract

VEGFR‐2 is a prominent therapeutic target in antitumor drug research to block tumor angiogenesis. This study focused on the synthesis and optimization of PROTACs based on the natural product rhein, resulting in the successful synthesis of 15 distinct molecules. In A549 cells, D9 exhibited remarkable antitumor efficacy with an IC50 of 5.88 ± 0.50 μM, which was 15‐fold higher compared to rhein (IC50=88.45 ± 2.77 μM). An in‐depth study of the effect of D9 on the degradation of VEGFR‐2 revealed that D9 was able to induce the degradation of VEGFR‐2 in A549 cells in a time‐dependent manner. The observed effect was reversible, contingent upon the proteasome and ubiquitination system, and demonstrably linked to CRBN. Further experiments revealed that D9 induced apoptosis in A549 cells and led to cell cycle arrest in the G1 phase. Molecular docking simulations validated the binding mode of D9 to VEGFR, establishing the potential of D9 to bind to VEGFR‐2 in its natural state. In summary, this study confirms the feasibility of natural product‐bound PROTAC technology for the development of a new generation of VEGFR‐2 degraders, offering a novel trajectory for the future development of pharmacological agents targeting VEGFR‐2.