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Structure-Based Discovery and Biological Assays of a Novel PRMT5 Inhibitor for Non-Small Cell Lung Cancer
Yingqing Chen1, Mingyu Zhang1, Anxin Wu1
1Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China.
Abstract:
Protein arginine methyltransferase 5 (PRMT5) is a popular anticancer target that regulates histone or nonhistone methylation and is linked to the development and poor prognosis of non-small cell lung cancer. PRMT5 inhibitors have shown great promise in clinical trials as a cancer therapy. However, most inhibitors reported recently act in a SAM-competitive mode and lack structural diversity. In this paper, a novel non-SAM inhibitor, 3039-0164, was discovered by the structure-based virtual screening method. The binding mechanism of 3039-0164 to PRMT5 was revealed via molecular docking and molecular dynamics simulations. 3039-0164 inhibited PRMT5 enzymatic activity, downregulated the expression of PRMT5 downstream target genes (FGFR3 and eIF4E), and blocked the activation of the PI3K/AKT/mTOR and ERK signaling pathways. The discovery of 3039-0164 provides precise and creative hit compounds for the design optimization of PRMT5 lead compounds in non-small cell lung cancer.
Insights
A novel non-SAM inhibitor, 3039-0164, was discovered for protein arginine methyltransferase 5 (PRMT5). This compound shows promise for non-small cell lung cancer therapy by inhibiting PRMT5 and its downstream pathways.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Protein arginine methyltransferase 5 (PRMT5) is a key regulator of methylation implicated in non-small cell lung cancer (NSCLC) development and prognosis.
- Existing PRMT5 inhibitors primarily function via SAM-competitive mechanisms, limiting structural diversity and therapeutic options.
- PRMT5 is a validated anticancer target, with inhibitors demonstrating clinical promise.
Purpose of the Study:
- To discover novel, non-SAM-competitive inhibitors of PRMT5.
- To elucidate the binding mechanism of a newly identified PRMT5 inhibitor.
- To evaluate the therapeutic potential of the novel inhibitor in NSCLC models.
Main Methods:
- Structure-based virtual screening was employed to identify potential PRMT5 inhibitors.
- Molecular docking and molecular dynamics simulations were used to analyze the binding interactions.
- In vitro enzymatic assays and cell-based assays were performed to assess inhibitory activity and downstream effects.
Main Results:
- A novel non-SAM inhibitor, 3039-0164, was identified through virtual screening.
- Molecular simulations revealed the binding mechanism of 3039-0164 to PRMT5.
- 3039-0164 demonstrated inhibition of PRMT5 activity, downregulation of FGFR3 and eIF4E, and blockade of PI3K/AKT/mTOR and ERK signaling pathways.
Conclusions:
- The discovery of 3039-0164 offers a novel chemical scaffold for PRMT5 inhibitor development.
- This non-SAM inhibitor provides a promising starting point for optimizing PRMT5-targeted therapies in NSCLC.
- The findings support the continued investigation of non-SAM PRMT5 inhibitors for cancer treatment.
