Abstract
CDC7, a serine-threonine kinase, plays conserved and important roles in regulation of DNA replication and has been recognized as a potential anticancer target. We report here the optimization of a series of furanone analogues starting from compound 1 with a focus on ADME properties suitable for clinical development. By replacing the 2-chlorobenzene moiety in 1 with various aliphatic groups, we identified compound 24 as a potent CDC7 inhibitor with excellent kinase selectivity and favorable oral bioavailability in multiple species. Oral administration of 24 demonstrated robust in vivo antitumor efficacy in a colorectal cancer xenograft model. Compound 24 (AS-0141) is currently in phase I clinical trials for the treatment of solid cancers.
MeSH terms
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Adenocarcinoma / drug therapy*
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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Dose-Response Relationship, Drug
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Drug Discovery*
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Female
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Humans
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Structure-Activity Relationship
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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CDC7 protein, human
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Protein Serine-Threonine Kinases