Divergent Polypharmacology-Driven Cellular Activity of Structurally Similar Multi-Kinase Inhibitors through Cumulative Effects on Individual Targets. Issue 9 (19th September 2019)

• Record Type: Journal Article
• Authors: Sumi, Natalia J.; Ctortecka, Claudia; Hu, Qianqian; Bryant, Annamarie T.; Fang, Bin; Remsing Rix, Lily L.; Ayaz, Muhammad; Kinose, Fumi; Welsh, Eric A.; Eschrich, Steven A.; Lawrence, Harshani R.; Koomen, John M.; Haura, Eric B.; Rix, Uwe
• Is Part Of: Cell chemical biology. Volume 26:Issue 9(2019)
• Page Start: 1240
• Page End: 1252.e11
• Publication Date: 2019-09-19
• Subjects: polypharmacology -- kinase inhibitor -- foretinib -- cabozantinib -- systems pharmacology -- chemoproteomics -- phosphoproteomics -- target selectivity -- lung cancer -- drug combination; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2019.06.003
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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, for MYC -amplified small-cell lung cancer. This systems pharmacology approach showed that small structural changes of drugs can cumulatively, through multiple targets, result in pronounced anticancer activity differences and that detailed mechanistic understanding of polypharmacology can enable repurposing opportunities for cancers with unmet medical need. Graphical Abstract: Highlights: Small structural change in multi-kinase drugs can cause strong cellular difference Functional proteomics and transcriptomics provide systems view of drug effects Systems pharmacology can elucidate differential mechanisms of related compounds Understanding polypharmacology can lead to repurposing of multi-targeted drugs Abstract : Sumi et al. use a systems polypharmacology approach involving chemical proteomics, phosphoproteomics, and RNA-seq to elucidate the differential mechanism of action of two multi-targeted drugs with similar chemical structure. The understanding of the polypharmacology mechanism of foretinib allowed for the rational development of a synergistic drug combination.