Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen.

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ICR Authors

Workman, Paul
 Raynaud, Florence
 Clarke, Paul
 Eccles, Suzanne

Authors

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

Document Type

Journal Article

Date

2015-02-26

Date Accepted

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.

Citation

Journal of medicinal chemistry, 2015, 58 (4), pp. 1717 - 1735

DOI

10.1021/jm501436m

URI

https://repository.icr.ac.uk/handle/internal/3885

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

AMER CHEMICAL SOC

ISSN

0022-2623

eISSN

1520-4804

Collections

Cancer Therapeutics

Research Team

Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Signal Transduction & Molecular Pharmacology
Tumour Biology & Metastasis

Notes