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Development of Novel PRMT7 Inhibitors for the Treatment of Prostate Cancer
Jiaxing Li1,2, Chengliang Sun1,2, Ying Zhang1,2
1State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Abstract:
Prostate cancer (PCa) remains a prevalent malignancy in men and warrants novel and efficacious therapy. Protein arginine methyltransferase 7 (PRMT7) has been recently identified as a promising target for PCa treatment, however, the development of efficacious PRMT7 inhibitors is limited. Herein, we reported an effective and selective PRMT7 inhibitor, A33, which was obtained through structural optimization and exhibited potent anti-PCa efficacy in vitro and in vivo. A33 significantly inhibited the proliferation, colony formation, migration, and invasion of PCa cells and induced substantial cell cycle arrest and apoptosis. Mechanistically, A33 decreased the monomethylarginine level in PCa cells, regulated tumor metastasis-, proliferation-, and apoptosis-associated proteins, and enhanced antitumor innate immunity by targeting PRMT7. More importantly, A33 exhibited low toxicity and effectively suppressed PCa tumor growth in the DU-145 xenograft tumor model. Collectively, this study provides a novel potent PRMT7 inhibitor for further anti-PCa drug discovery.
Insights
A novel drug candidate, A33, effectively targets Protein arginine methyltransferase 7 (PRMT7) to inhibit prostate cancer (PCa) growth. This PRMT7 inhibitor shows potent anti-PCa efficacy with low toxicity in preclinical models.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Prostate cancer (PCa) is a common malignancy requiring new treatments.
- Protein arginine methyltransferase 7 (PRMT7) is a potential therapeutic target for PCa.
- Developing effective PRMT7 inhibitors for PCa has been challenging.
Purpose of the Study:
- To develop and evaluate a novel, selective inhibitor of PRMT7 for prostate cancer therapy.
- To assess the in vitro and in vivo efficacy of the PRMT7 inhibitor A33 against PCa.
- To elucidate the mechanism of action of A33 in PCa cells.
Main Methods:
- Structural optimization was used to identify and develop the PRMT7 inhibitor A33.
- In vitro assays were performed to evaluate PCa cell proliferation, colony formation, migration, and invasion.
- In vivo studies utilized a DU-145 xenograft tumor model to assess A33's efficacy and toxicity.
Main Results:
- A33 demonstrated significant inhibition of PCa cell proliferation, colony formation, migration, and invasion.
- A33 induced cell cycle arrest and apoptosis in PCa cells.
- A33 suppressed PCa tumor growth in vivo with low toxicity and enhanced antitumor immunity.
Conclusions:
- A33 is a potent and selective PRMT7 inhibitor with significant anti-PCa efficacy.
- A33 represents a promising therapeutic candidate for prostate cancer drug discovery.
- Targeting PRMT7 with A33 offers a novel strategy for treating prostate cancer.
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