Chemogenomic library design strategies for precision oncology, applied to phenotypic profiling of glioblastoma patient cells
Paschalis Athanasiadis,
Balaguru Ravikumar,
Richard J.R. Elliott,
John C. Dawson,
Neil O. Carragher,
Paul A. Clemons,
Timothy Johanssen,
Daniel Ebner,
Tero Aittokallio
Affiliations
Paschalis Athanasiadis
Institute for Cancer Research, Department of Cancer Genetics, Oslo University Hospital, 0310 Oslo, Norway; Centre for Biostatistics and Epidemiology (OCBE), Faculty of Medicine, University of Oslo, 0317 Oslo, Norway
Balaguru Ravikumar
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 20520 00290 Helsinki, Finland
Richard J.R. Elliott
Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XR, UK
John C. Dawson
Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XR, UK
Neil O. Carragher
Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XR, UK
Paul A. Clemons
Chemical Biology and Therapeutics Science Program, Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, United States
Timothy Johanssen
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
Daniel Ebner
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
Tero Aittokallio
Institute for Cancer Research, Department of Cancer Genetics, Oslo University Hospital, 0310 Oslo, Norway; Centre for Biostatistics and Epidemiology (OCBE), Faculty of Medicine, University of Oslo, 0317 Oslo, Norway; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, 20520 00290 Helsinki, Finland; Corresponding author
Summary: 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.
