Phenotypic Screening of Chemical Libraries Enriched by Molecular Docking to Multiple Targets Selected from Glioblastoma Genomic Data

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.