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Published on: March 28, 2021
Structure-Guided Discovery of a Bis-Pyridyl Diamine-Based Dual CDK7/9 Inhibitor with In Vitro and In Vivo Antitumor
Nithya Sree Pr1, Tejaswi Somarowthu2,3, Jeyasankari S1
1Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India.
Abstract:
Glioblastoma multiforme (GBM) is a lethal and fast-growing brain cancer that is difficult to treat with standard medical interventions. GBM tumors often overexpress cyclin-dependent kinase 9, in complex with cyclin T1, and thus, it represents a promising target for therapeutic intervention. In this study, we employed a structure-based virtual screening approach for a curated library of 6,059 bis-pyridyl compounds from PubChem to identify potential CDK9/T1 inhibitors. Subsequent in vitro ADP-Glo assay led to the identification of GNE-3511 as a potent CDK9/T1 inhibitor with an IC50 of 0.064 μM. GNE-3511 also inhibited CDK7/cyclin H with an IC50 of 0.12 μM. In U-87 MG and T98G glioblastoma cells, GNE-3511 exhibited cytotoxicity with a GI50 of 3.4 and 5.0 μM, inducing G2/M phase cell cycle arrest and promoting early apoptosis. Treatment with GNE-3511 significantly reduced the expression of the anti-apoptotic markers BCL-2, SURVIVIN and drug resistance markers (ABCB1 and ABCG2) in a dose-dependent manner, and downregulated glioma stem cell population/markers (CD44, CD90+, or CD133+ and BMI-1) and sphere formation abilities. Oral administration of GNE-3511 at 20 mg/kg (twice daily) demonstrated significant anti-tumor efficacy and improved survival in both U-87 MG and T98G xenograft/orthotopic mouse models. Collectively, these findings highlight GNE-3511 as a promising lead candidate for the development of GBM therapeutics.
Insights
A novel compound, GNE-3511, effectively inhibits cyclin-dependent kinase 9/T1 (CDK9/T1) in glioblastoma cells. This drug candidate shows significant anti-tumor activity and improves survival in preclinical models of brain cancer.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain cancer with limited treatment options.
- Overexpression of cyclin-dependent kinase 9/T1 (CDK9/T1) in GBM presents a potential therapeutic target.
Purpose of the Study:
- To identify novel inhibitors of CDK9/T1 using structure-based virtual screening.
- To evaluate the efficacy of identified inhibitors in preclinical GBM models.
Main Methods:
- Structure-based virtual screening of 6,059 bis-pyridyl compounds identified GNE-3511.
- In vitro assays assessed CDK9/T1 inhibition (IC50), cytotoxicity (GI50), cell cycle arrest, and apoptosis.
- Western blotting analyzed the expression of apoptosis, drug resistance, and glioma stem cell markers.
- In vivo studies evaluated GNE-3511 efficacy in xenograft and orthotopic GBM mouse models.
Main Results:
- GNE-3511 potently inhibited CDK9/T1 (IC50 = 0.064 μM) and CDK7/cyclin H (IC50 = 0.12 μM).
- GNE-3511 demonstrated cytotoxicity in GBM cells, inducing G2/M arrest and apoptosis.
- The compound reduced anti-apoptotic and drug resistance markers, and downregulated glioma stem cell populations.
- GNE-3511 exhibited significant anti-tumor efficacy and improved survival in preclinical GBM models.
Conclusions:
- GNE-3511 is a potent CDK9/T1 inhibitor with significant preclinical anti-glioblastoma activity.
- GNE-3511 warrants further development as a potential therapeutic agent for GBM.
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