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, AD4, the most potent compound, exhibited an IC 50 value of 50.6 nM in RS4;11 cells, over 12-fold better than that of its parent compound, SM1044. This was supported by prolonged survival of RS4;11-transplanted NOD/SCID mice. Meanwhile, AD4 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 AD4 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.

Design, docking optimization, and evaluation of biotin-PEG4-1,8-naphthalimide as a potent and safe antitumor agent with dual targeting of ferroptosis and DNA

“…Generally, scores greater than 4 indicated that the active concentration was at the micromolar level, whereas scores greater than 7 meant that the active concentration was at the nanomolar level. 30 As shown in Fig. 2, the docking results from the DNA: 182D-model revealed that biotin-PEG-piperazine-1,8-naphthalimides with two, four, and five units of PEG linker exhibited good intercalation with DNA, with the score values of more than 8.…”

“…A score greater than 4 indicated a valid intercalation effect. 30 This was compared with the score obtained using the intermediate of 4 piperazine-1,8-naphthalimide ( 8 , Scheme 1). Generally, scores greater than 4 indicated that the active concentration was at the micromolar level, whereas scores greater than 7 meant that the active concentration was at the nanomolar level.…”

Ring‐Contracted Artemisinin Derivatives as Novel CDK 4/6 Inhibitors: Synthesis and Anti‐Breast Cancer Evaluation

“…[5,6] The effects of these compounds on cell-cycle arrest have also been reported previously. [7][8][9] Although there is no unified understanding of the anti-tumor mechanism of artemisinins in the academic community, it is generally believed that the endoperoxide group of artemisinins plays an important role both in anti-tumor effects and in anti-malarial activities. [10,11] Intriguingly, D-ring-contracted artemisinin derivatives (nonhemiacetal derivatives) have been reported to be safer and more stable than their hemiacetal counterparts (derivatives of dihydroartemisinin).…”