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Updated: Sep 26, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Discovery and Evaluation of Novel Angular Fused Pyridoquinazolinonecarboxamides as RNA Polymerase I Inhibitors
Tony E Dorado1, Pablo de León2, Asma Begum3
1Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218, United States.
Abstract:
RNA polymerase I (Pol I) transcribes ribosomal DNA (rDNA) into the 47S ribosomal RNA (rRNA) precursor. Further processing produces the 28S, 5.8S, and 18S rRNAs that are assembled into mature ribosomes. Many cancers exhibit higher Pol I transcriptional activity, reflecting a need for increased ribosome biogenesis and protein synthesis and making the inhibition of this process an attractive therapeutic strategy. Lead molecule BMH-21 (1) has been established as a Pol I inhibitor by affecting the destruction of RPA194, the Pol I large catalytic subunit. A previous structure-activity relationship (SAR) study uncovered key pharmacophores, but activity was constrained within a tight chemical space. This work details further SAR efforts that have yielded new scaffolds and improved off-target activity while retaining the desired RPA194 degradation potency. Pharmacokinetic profiling was obtained and provides a starting point for further optimization. New compounds present additional opportunities for the development of Pol I inhibitory cancer therapies.
Insights
Researchers developed new compounds that inhibit RNA polymerase I (Pol I) by degrading its RPA194 subunit. These novel scaffolds offer improved properties for developing targeted cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- RNA polymerase I (Pol I) drives ribosome biogenesis, crucial for cancer cell proliferation.
- Elevated Pol I activity is a hallmark of many cancers, making it a therapeutic target.
- Previous inhibitors, like BMH-21, showed promise but were limited by chemical space.
Purpose of the Study:
- To explore new chemical scaffolds for Pol I inhibition.
- To improve off-target activity while maintaining RPA194 degradation.
- To identify lead compounds for Pol I-targeted cancer therapy.
Main Methods:
- Structure-activity relationship (SAR) studies were conducted on Pol I inhibitors.
- New molecular scaffolds were synthesized and evaluated.
- Pharmacokinetic profiling was performed on promising compounds.
Main Results:
- Novel chemical scaffolds with Pol I inhibitory activity were identified.
- Compounds demonstrated improved off-target profiles.
- RPA194 degradation potency was successfully retained.
- Pharmacokinetic data provides a basis for further optimization.
Conclusions:
- New Pol I inhibitors with enhanced properties were developed.
- These compounds represent promising candidates for cancer therapy.
- Further optimization could lead to clinically viable Pol I-targeting drugs.
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