Abstract
In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-d]pyrimidinone analogue I showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chemistry efforts led to the identification of compound 3d, which exhibited potent cellular activity, excellent kinase selectivity, and antitumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed study of 3d, which was deemed an obstacle to further development. A structure-based approach to circumvent the adduct formation culminated in the discovery of compound 11b (TAK-931) possessing a quinuclidine moiety as a preclinical candidate. In this paper, the design, synthesis, and biological evaluation of this series of compounds will be presented.
Publication types
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Research Support, N.I.H., Extramural
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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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Binding Sites
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / chemistry
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Drug Design
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Drug Discovery
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Formaldehyde / chemistry
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Humans
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Mice
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Molecular Docking Simulation
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Molecular Structure
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / metabolism
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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 / chemistry
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Protein Serine-Threonine Kinases / metabolism
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Pyrazolones / pharmacology
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Pyrazolones / therapeutic use*
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Pyrimidines / pharmacology
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Pyrimidines / therapeutic use*
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Pyrimidinones / chemical synthesis
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Pyrimidinones / metabolism
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Pyrimidinones / therapeutic use*
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Quinuclidines / chemical synthesis
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Quinuclidines / metabolism
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Quinuclidines / therapeutic use*
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Structure-Activity Relationship
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Thiophenes / chemical synthesis
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Thiophenes / metabolism
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Thiophenes / therapeutic use*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Cell Cycle Proteins
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Protein Kinase Inhibitors
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Pyrazolones
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Pyrimidines
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Pyrimidinones
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Quinuclidines
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Thiophenes
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Formaldehyde
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CDC7 protein, human
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Protein Serine-Threonine Kinases
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simurosertib