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

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

  • Cell Chem Biol. 2019 Sep 19;26(9):1240-1252.e11. doi: 10.1016/j.chembiol.2019.06.003.
Natalia J Sumi 1,  Claudia Ctortecka 2,  Qianqian Hu 1,  Annamarie T Bryant 2,  Bin Fang 3,  Lily L Remsing Rix 2,  Muhammad Ayaz 4,  Fumi Kinose 5,  Eric A Welsh 6,  Steven A Eschrich 7,  Harshani R Lawrence 8,  John M Koomen 9,  Eric B Haura 5,  Uwe Rix 10
Affiliations

Affiliations

  • 1 Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL 33620, USA.
  • 2 Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 3 Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 4 Chemical Biology Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 5 Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 6 Biostatistics and Bioinformatics Shared Resource, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 7 Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA.
  • 8 Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Chemical Biology Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA.
  • 9 Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA; Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 10 Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA. Electronic address: uwe.rix@moffitt.org.
PMID: 31257184 DOI: 10.1016/j.chembiol.2019.06.003
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, 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.

Keywords

cabozantinib; chemoproteomics; drug combination; foretinib; kinase inhibitor; lung cancer; phosphoproteomics; polypharmacology; systems pharmacology; target selectivity.

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