Abstract
WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Biological Assay / methods
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Biological Availability
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology
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Crystallography, X-Ray
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical / methods*
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Humans
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Luciferases / antagonists & inhibitors*
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Luciferases / metabolism
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Mice
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Models, Molecular
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Molecular Structure
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Pyridines / administration & dosage
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Pyridines / chemistry
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Pyridines / pharmacology*
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Small Molecule Libraries / administration & dosage
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Spiro Compounds / administration & dosage
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacology*
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Structure-Activity Relationship
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Wnt Signaling Pathway / drug effects*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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CCT251545
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Pyridines
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Small Molecule Libraries
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Spiro Compounds
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Luciferases