Facilitated Drug Repurposing with Artemisinin-Derived PROTACs: Unveiling PCLAF as a Therapeutic Target

Abstract

Artemisinin, a prominent anti-malaria drug, is being investigated for its potential as a repurposed cancer treatment. However, its effectiveness in tumor cell lines remains limited, and its mechanism of action is unclear. To make more progress, the PROteolysis-TArgeting chimera (PROTAC) technique has been applied to design and synthesize novel artemisinin derivatives in this study. Among them, <b>AD4</b>, the most potent compound, exhibited an IC₅₀ value of 50.6 nM in RS4;11 cells, over 12-fold better than that of its parent compound, <b>SM1044</b>. This was supported by prolonged survival of RS4;11-transplanted NOD/SCID mice. Meanwhile, <b>AD4</b> effectively degraded PCLAF in RS4;11 cells and thus activated the p21/Rb axis to exert antitumor activity by directly targeting PCLAF. The discovery of <b>AD4</b> highlights the great potential of using PROTACs to improve the efficacy of natural products, identify therapeutic targets, and facilitate drug repurposing. This opens a promising avenue for transforming other natural products into effective therapies.