Studies from Dr. Zhiyuan Zhang’s laboratory revealed GSTO1 as the target of piperlongumine in selective killing cancer

In the current issue of Chemical Communications available from April 9^th 2019, Dr. Zhiyuan Zhang from NIBS published a research article entitled “Activity-based Protein Profiling Reveals GSTO1 as the Covalent Target of Piperlongumine and a Promising Target for Combination Therapy for Cancer”. In this paper, the authors revealed the natural product piperlongumine functions through covalently inhibit GSTO1 to selectively kill cancer cells and also discovered that GSTO1 is a promising target for combine therapy towards cancer.

Piperlongumine (PL-1), an alkaloid natural product from Piper longum, is reported to kill a large variety of cancer cells while remaining nontoxic to normal cells. The cancer cell death induction effect of PL-1 was demonstrated in in vivo xenograft models of numerous cancer cell types, indicating that PL-1 is a potential lead anti-cancer compound. Up to now, the functional target and precise molecular mechanism responsible for PL-1’s selective cancer killing effects still remains unclear.

The authors initially determined that PL-1 binds covalently to its (unspecified) cellular target through SAR study and model reaction study. Then they designed an active alkynylated analogue of PL-1 as a probe for click-reaction-assisted ABPP. Subsequently, Glutathione S-transferase omega-1 (GSTO1) was identified and verified as the functional covalent target of PL-1. Biochemical study further revealed that PL-1 induces cancer cell death via inhibition of GSTO1 through specifically binding the Cys32, the catalytic site of GSTO1. These results together offer a coherent mechanistic explanation for the observed anticancer performance of PL-1. Importantly, though a large-scale drug combination screen using PL-1 as a GSTO1 inhibitor and tool compound, this study also discovered that GSTO1 inhibition has unexpectedly broad-spectrum synergistic effects with a large proportion of anti-cancer drugs especially with PI3K/Akt/mTOR pathway inhibitors, and yielded important basic and clinically relevant insights.

The postdoc Li Li from Dr. Zhiyuan Zhang’s lab is the first author of this article. Other contributors include Yue Zhao, Lin Li, Gaihong Cai, Dr. She Chen from the Proteomic Center and Jiaojiao Li and Dr. Xiangbing Qi from the Chemical Center. Dr. Zhiyuan Zhang is the corresponding author for this article. This project was supported by Chinese Ministry of Science and Technology and Beijing Government, and was carried out at the National Institute of Biological Sciences, Beijing.