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High-throughput Screening for Chemical Modulators of Post-transcriptionally Regulated Genes
Published on: March 3, 2015
Phenotypic Screening of Chemical Libraries Enriched by Molecular Docking to Multiple Targets Selected from
David Xu1,2, Donghui Zhou3, Khuchtumur Bum-Erdene3
1Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States.
Abstract:
Like most solid tumors, glioblastoma multiforme (GBM) harbors multiple overexpressed and mutated genes that affect several signaling pathways. Suppressing tumor growth of solid tumors like GBM without toxicity may be achieved by small molecules that selectively modulate a collection of targets across different signaling pathways, also known as selective polypharmacology. Phenotypic screening can be an effective method to uncover such compounds, but the lack of approaches to create focused libraries tailored to tumor targets has limited its impact. Here, we create rational libraries for phenotypic screening by structure-based molecular docking chemical libraries to GBM-specific targets identified using the tumor's RNA sequence and mutation data along with cellular protein-protein interaction data. Screening this enriched library of 47 candidates led to several active compounds, including 1 (IPR-2025), which (i) inhibited cell viability of low-passage patient-derived GBM spheroids with single-digit micromolar IC50 values that are substantially better than standard-of-care temozolomide, (ii) blocked tube-formation of endothelial cells in Matrigel with submicromolar IC50 values, and (iii) had no effect on primary hematopoietic CD34+ progenitor spheroids or astrocyte cell viability. RNA sequencing provided the potential mechanism of action for 1, and mass spectrometry-based thermal proteome profiling confirmed that the compound engages multiple targets. The ability of 1 to inhibit GBM phenotypes without affecting normal cell viability suggests that our screening approach may hold promise for generating lead compounds with selective polypharmacology for the development of treatments of incurable diseases like GBM.
Insights
Researchers developed a new screening method to find drugs that target glioblastoma multiforme (GBM). This approach identified a compound that effectively inhibits GBM growth without harming healthy cells, offering a promising new avenue for cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Glioblastoma multiforme (GBM) is a solid tumor with multiple genetic alterations affecting key signaling pathways.
- Selective polypharmacology, modulating multiple targets with small molecules, offers a strategy to suppress tumor growth without toxicity.
- Current phenotypic screening methods are limited by the lack of focused compound libraries tailored to specific tumor targets.
Purpose of the Study:
- To develop a rational approach for creating focused compound libraries for phenotypic screening against GBM.
- To identify novel compounds with selective polypharmacology for glioblastoma treatment.
Main Methods:
- Structure-based molecular docking of chemical libraries to GBM-specific targets identified from RNA sequencing, mutation data, and protein-protein interaction data.
- Phenotypic screening of an enriched library of 47 candidates against patient-derived GBM spheroids and normal cells.
- RNA sequencing and mass spectrometry-based thermal proteome profiling to elucidate the mechanism of action and target engagement.
Main Results:
- Identified compound 1 (IPR-2025) inhibited GBM spheroid viability with low micromolar IC50 values, outperforming temozolomide.
- Compound 1 effectively blocked endothelial cell tube formation (submicromolar IC50) but showed no toxicity to hematopoietic progenitor or astrocyte cells.
- Mechanism of action studies confirmed compound 1 engages multiple targets and exhibits selective polypharmacology.
Conclusions:
- The structure-based library design approach successfully identified a potent GBM inhibitor with selective polypharmacology.
- Compound 1 demonstrates significant potential as a lead compound for developing novel glioblastoma treatments.
- This screening strategy may be applicable to discovering treatments for other incurable diseases.
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