Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen.
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Date
2015-02-26Author
Mallinger, A
Crumpler, S
Pichowicz, M
Waalboer, D
Stubbs, M
Adeniji-Popoola, O
Wood, B
Smith, E
Thai, C
Henley, AT
Georgi, K
Court, W
Hobbs, S
Box, G
Ortiz-Ruiz, M-J
Valenti, M
De Haven Brandon, A
TePoele, R
Leuthner, B
Workman, P
Aherne, W
Poeschke, O
Dale, T
Wienke, D
Esdar, C
Rohdich, F
Raynaud, F
Clarke, PA
Eccles, SA
Stieber, F
Schiemann, K
Blagg, J
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Animals
Humans
Mice
Colorectal Neoplasms
Disease Models, Animal
Pyridines
Spiro Compounds
Luciferases
Antineoplastic Agents
Biological Assay
Crystallography, X-Ray
Administration, Oral
Drug Evaluation, Preclinical
Xenograft Model Antitumor Assays
Cell Proliferation
Molecular Structure
Structure-Activity Relationship
Biological Availability
Dose-Response Relationship, Drug
Models, Molecular
Small Molecule Libraries
Wnt Signaling Pathway
Research team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Signal Transduction & Molecular Pharmacology
Tumour Biology & Metastasis
Language
eng
License start date
2015-02-13
Citation
Journal of medicinal chemistry, 2015, 58 (4), pp. 1717 - 1735
Publisher
AMER CHEMICAL SOC