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Published on: December 26, 2016
Discovery of novel and potent celastrol derivatives as PRDX1 inhibitors for cancer therapy through structure-based
Lixia Guan1, Yifei Geng1, Yuting Wang1
1Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China.
Background:
Peroxiredoxin 1 (PRDX1) is an antioxidant enzyme overexpressed in several cancers that protects tumor cells from oxidative damage by scavenging excess reactive oxygen species making it a potential strategy for cancer therapy.
Methods:
In this study, a multi-step screening strategy combining molecular docking, enzyme inhibition assay, enzyme kinetic studies, molecular dynamics (MD) simulations, MST assays, MTT assays and in vivo toxicity assay was used to discover PRDX1 inhibitors.
Results:
Five compounds (CPs 1-5) targeting PRDX1 were identified through molecular docking screening. CPs 1-5 showed significant PRDX1 inhibition at the nanomolar level. Among them, CP1 exhibited the most potent inhibitory activity (IC50 = 0.08 ± 0.01 nM) and high selectivity against PRDX1. The kinetic study showed that CP1 acted as noncompetitive PRDX1 inhibitor. MD simulations confirmed the stability of the CP1-PRDX1 complex. MST assays revealed that CP1 displayed a significant binding affinity for PRDX1 (K d = 0.06 ± 0.001 nM). Importantly, CP1 exhibited significant antiproliferative effects on A549, HepG2 and MCF-7 tumor cells without toxicity to other normal cells. Meanwhile, CP1 did not exhibit significant hepatotoxicity or renal toxicity in mice.
Conclusion:
The results suggest that CP1 is a promising antitumor candidate for cancer therapy and merits further investigation.
Insights
Researchers discovered a potent new compound, CP1, that inhibits the antioxidant enzyme Peroxiredoxin 1 (PRDX1). This PRDX1 inhibitor shows significant anti-cancer effects and minimal toxicity, making it a promising candidate for cancer therapy.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Peroxiredoxin 1 (PRDX1) is an antioxidant enzyme.
- PRDX1 is overexpressed in various cancers, protecting tumor cells from oxidative stress.
- Targeting PRDX1 presents a potential cancer therapy strategy.
Purpose of the Study:
- To discover novel inhibitors of Peroxiredoxin 1 (PRDX1).
- To evaluate the efficacy and safety of identified PRDX1 inhibitors.
- To explore the potential of PRDX1 inhibition in cancer treatment.
Main Methods:
- A multi-step screening strategy was employed, including molecular docking, enzyme inhibition assays, kinetic studies, and molecular dynamics simulations.
- MST assays, MTT assays, and in vivo toxicity studies were conducted.
- Five compounds (CPs 1-5) targeting PRDX1 were identified.
Main Results:
- CP1 demonstrated potent PRDX1 inhibition at nanomolar levels (IC50 = 0.08 ± 0.01 nM) with high selectivity.
- Molecular dynamics simulations confirmed the stability of the CP1-PRDX1 complex, and MST assays showed strong binding affinity (Kd = 0.06 ± 0.001 nM).
- CP1 exhibited significant antiproliferative effects on A549, HepG2, and MCF-7 cancer cells without significant toxicity to normal cells or in vivo hepatotoxicity/renal toxicity in mice.
Conclusions:
- CP1 is a highly effective and selective PRDX1 inhibitor.
- CP1 demonstrates significant antitumor activity with a favorable safety profile.
- CP1 warrants further investigation as a potential therapeutic agent for cancer treatment.
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