Abstract
Triple negative breast cancer (TNBC) is an aggressive disease with high relapse rates and few treatment options. Outlined in previous publications, we identified a series of potent, dual TTK/CLK2 inhibitors with strong efficacy in TNBC xenograft models. Pharmacokinetic properties and kinome selectivity were optimized, resulting in the identification of a new series of potent, selective, and orally bioavailable TTK inhibitors. We describe here the structure-activity relationship of the 2,4-disubstituted-7 H-pyrrolo[2,3- d]pyrimidine series, leading to significant single agent efficacy in a TNBC xenograft model without body weight loss. The design effort evolving an iv-dosed TTK/CLK2 inhibitor to an orally bioavailable TTK inhibitor is described.
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 / pharmacokinetics
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Antineoplastic Agents / therapeutic use*
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Apoptosis / drug effects
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Docetaxel / therapeutic use
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Drug Design
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Female
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Mice, SCID
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Microtubule-Associated Proteins / metabolism
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Molecular Structure
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / therapeutic use*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Pyrimidines / chemical synthesis
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Pyrimidines / pharmacokinetics
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Pyrimidines / therapeutic use*
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Pyrroles / chemical synthesis
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Pyrroles / pharmacokinetics
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Pyrroles / therapeutic use*
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Rats
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Structure-Activity Relationship
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Triple Negative Breast Neoplasms / drug therapy*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Knl1 protein, mouse
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Microtubule-Associated Proteins
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Protein Kinase Inhibitors
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Pyrimidines
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Pyrroles
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Docetaxel
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Ttk protein, mouse
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Protein Serine-Threonine Kinases