Sirtuin 6 (SIRT6) is an NAD+-dependent deacetylase with a significant role in 20% of all cancers, such as colon cancers and rectal adenocarcinoma. However, there is currently no effective drug for cancers related to SIRT6. To explore potential inhibitors of SIRT6, it is essential to reveal details of the interaction mechanisms between inhibitors and SIRT6 at the atomic level. The nature of small molecules from herbs have many advantages as inhibitors. Based on the conformational characteristics of the inhibitor Compound 9 (Asinex ID: BAS13555470), we explored the natural molecule Scutellarin, one compound of Huang Qin, which is an effective herb for curing cancer that has been described in the Traditional Chinese Medicine (TCMS) library. We investigated the interactions between SIRT6 and the inhibitors using molecular dynamics (MD) simulations. We illustrated that the structurally similar inhibitors have a similar binding mode to SIRT6 with residues—Leu9, Phe64, Val115, His133 and Trp188. Hydrophobic and π-stacking interactions play important roles in the interactions between SIRT6 and inhibitors. In summary, our results reveal the interactive mechanism of SIRT6 and the inhibitors and we also provide Scutellarin as a new potential inhibitor of SIRT6. Our study provides a new potential way to explore potential inhibitors from TCMS.

The multitask model predicts the reaction on low-resource datasets, and the accuracy is significantly higher than that of the baseline model.

Pancreatic cancer remains one of the most lethal malignancies in the digestive system, with limited available drugs and a need for improved efficacy. This unmet clinical need highlights the urgency to discover novel, highly efficient small‐molecule compounds. Herein, a novel cyano‐containing artemisinin dimer derivative, ZQJ29, is synthesized through structural modifications of artemisinin. Biological evaluation demonstrated that ZQJ29 effectively inhibits the proliferation of pancreatic cancer cells both in vitro and in vivo. ZQJ29 selectively targets PARP1 and has distinct structural features comparable to established PARP1 inhibitors such as Olaparib. Notably, ZQJ29 is the first reported artemisinin derivative to inhibit PARP1. Furthermore, the inhibition of PARP1 by ZQJ29 enhances the expression of TP53 and inhibits the SLC7A11/GPX4 pathway. The work first demonstrates that targeting PARP1 can induce ferroptosis in pancreatic cancer. These findings not only identify promising artemisinin derivatives for the development of therapies targeting pancreatic cancer but also provide scientific evidence supporting therapeutic strategies aimed at inducing ferroptosis in pancreatic cancer. This research lays a robust foundation for subsequent preclinical studies.