Abstract
Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / therapeutic use*
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Cell Line, Tumor
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Drug Design
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / therapeutic use*
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Female
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Humans
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Isocitrate Dehydrogenase / antagonists & inhibitors*
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Isocitrate Dehydrogenase / metabolism
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Mice, Inbred BALB C
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Molecular Structure
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Neoplasms / drug therapy*
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Protein Binding
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Pyridines / chemical synthesis
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Pyridines / metabolism
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Pyridines / therapeutic use*
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Quinolines / chemical synthesis
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Quinolines / metabolism
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Quinolines / therapeutic use*
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Quinolones / chemical synthesis
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Quinolones / metabolism
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Quinolones / therapeutic use*
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Pyridines
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Quinolines
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Quinolones
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olutasidenib
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Isocitrate Dehydrogenase
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IDH1 protein, human