Chemogenomic library design strategies for precision oncology, applied to phenotypic profiling of glioblastoma patient cells

Designing a targeted screening library of bioactive small molecules is a challenging task since most compounds modulate their effects through multiple protein targets with varying degrees of potency and selectivity. We implemented analytic procedures for designing anticancer compound libraries adjusted for library size, cellular activity, chemical diversity and availability, and target selectivity. The resulting compound collections cover a wide range of protein targets and biological pathways implicated in various cancers, making them widely applicable to precision oncology. We characterized the compound and target spaces of the virtual libraries, in comparison with a minimal screening library of 1,211 compounds for targeting 1,386 anticancer proteins. In a pilot screening study, we identified patient-specific vulnerabilities by imaging glioma stem cells from patients with glioblastoma (GBM), using a physical library of 789 compounds that cover 1,320 of the anticancer targets. The cell survival profiling revealed highly heterogeneous phenotypic responses across the patients and GBM subtypes.

Automated summary

Designing a targeted screening library of bioactive small molecules is a challenging task due to the complexity of compound-protein interactions. In this study, we developed analytic procedures to design anticancer compound libraries that consider factors such as library size, cellular activity, chemical diversity, and target selectivity. The resulting compound collections cover a wide range of protein targets and biological pathways implicated in various cancers, making them valuable for precision oncology. In a pilot screening study, we identified patient-specific vulnerabilities using a physical library of compounds, highlighting the heterogeneity of phenotypic responses across patients and glioblastoma subtypes.