Divergent Polypharmacology-Driven Cellular Activity of Structurally Similar Multi-Kinase Inhibitors through Cumulative Effects on Individual Targets.

ABSTRACT: Despite recent successes of precision and immunotherapies there is a persisting need for novel targeted or multi-targeted approaches in complex diseases. Through a systems pharmacology approach, including phenotypic screening, chemical and phosphoproteomics, and RNA-seq, we elucidated the targets and mechanisms underlying the differential anticancer activity of two structurally related multi-kinase inhibitors, foretinib, and cabozantinib, in lung cancer cells. Biochemical and cellular target validation using probe molecules and RNAi revealed a polypharmacology mechanism involving MEK1/2, FER, and AURKB, which were each more potently inhibited by foretinib than cabozantinib. Based on this, we developed a synergistic combination of foretinib with barasertib, a more potent AURKB inhibitor, fo

SUBMITTER: Sumi NJ 

PROVIDER: S-EPMC6754293 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature