Abstract
Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, in vivo efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / therapeutic use*
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Axl Receptor Tyrosine Kinase
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Screening Assays, Antitumor
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Female
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Imidazoles / chemical synthesis
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Imidazoles / therapeutic use*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Nude
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Molecular Structure
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Neoplasms / drug therapy*
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / therapeutic use*
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Proto-Oncogene Proteins / metabolism
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Pyridines / chemical synthesis
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Pyridines / therapeutic use*
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Receptor Protein-Tyrosine Kinases / metabolism
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Structure-Activity Relationship
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c-Mer Tyrosine Kinase / metabolism
Substances
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Antineoplastic Agents
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Imidazoles
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyridines
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Mertk protein, mouse
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Receptor Protein-Tyrosine Kinases
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c-Mer Tyrosine Kinase
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Axl Receptor Tyrosine Kinase
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AXL receptor tyrosine kinase, mouse