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

Artemisinin, a prominent anti-malaria drug, is beinginvestigatedfor its potential as a repurposed cancer treatment. However, its effectivenessin tumor cell lines remains limited, and its mechanism of action isunclear. To make more progress, the PROteolysis-TArgeting chimera(PROTAC) technique has been applied to design and synthesize novelartemisinin derivatives in this study. Among them, AD4, the most potent compound, exhibited an IC50 value of50.6 nM in RS4;11 cells, over 12-fold better than that of its parentcompound, SM1044. This was supported by prolonged survivalof RS4;11-transplanted NOD/SCID mice. Meanwhile, AD4 effectivelydegraded PCLAF in RS4;11 cells and thus activated the p21/Rb axisto exert antitumor activity by directly targeting PCLAF. The discoveryof AD4 highlights the great potential of using PROTACsto improve the efficacy of natural products, identify therapeutictargets, and facilitate drug repurposing. This opens a promising avenuefor transforming other natural products into effective therapies.