dc.contributor.author | Mallinger, A | |
dc.contributor.author | Crumpler, S | |
dc.contributor.author | Pichowicz, M | |
dc.contributor.author | Waalboer, D | |
dc.contributor.author | Stubbs, M | |
dc.contributor.author | Adeniji-Popoola, O | |
dc.contributor.author | Wood, B | |
dc.contributor.author | Smith, E | |
dc.contributor.author | Thai, C | |
dc.contributor.author | Henley, AT | |
dc.contributor.author | Georgi, K | |
dc.contributor.author | Court, W | |
dc.contributor.author | Hobbs, S | |
dc.contributor.author | Box, G | |
dc.contributor.author | Ortiz-Ruiz, M-J | |
dc.contributor.author | Valenti, M | |
dc.contributor.author | De Haven Brandon, A | |
dc.contributor.author | TePoele, R | |
dc.contributor.author | Leuthner, B | |
dc.contributor.author | Workman, P | |
dc.contributor.author | Aherne, W | |
dc.contributor.author | Poeschke, O | |
dc.contributor.author | Dale, T | |
dc.contributor.author | Wienke, D | |
dc.contributor.author | Esdar, C | |
dc.contributor.author | Rohdich, F | |
dc.contributor.author | Raynaud, F | |
dc.contributor.author | Clarke, PA | |
dc.contributor.author | Eccles, SA | |
dc.contributor.author | Stieber, F | |
dc.contributor.author | Schiemann, K | |
dc.contributor.author | Blagg, J | |
dc.date.accessioned | 2020-07-28T14:07:04Z | |
dc.date.issued | 2015-02-26 | |
dc.identifier.citation | Journal of medicinal chemistry, 2015, 58 (4), pp. 1717 - 1735 | |
dc.identifier.issn | 0022-2623 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3885 | |
dc.identifier.eissn | 1520-4804 | |
dc.identifier.doi | 10.1021/jm501436m | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 1717 - 1735 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER CHEMICAL SOC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Colorectal Neoplasms | |
dc.subject | Disease Models, Animal | |
dc.subject | Pyridines | |
dc.subject | Spiro Compounds | |
dc.subject | Luciferases | |
dc.subject | Antineoplastic Agents | |
dc.subject | Biological Assay | |
dc.subject | Crystallography, X-Ray | |
dc.subject | Administration, Oral | |
dc.subject | Drug Evaluation, Preclinical | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Cell Proliferation | |
dc.subject | Molecular Structure | |
dc.subject | Structure-Activity Relationship | |
dc.subject | Biological Availability | |
dc.subject | Dose-Response Relationship, Drug | |
dc.subject | Models, Molecular | |
dc.subject | Small Molecule Libraries | |
dc.subject | Wnt Signaling Pathway | |
dc.title | Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1021/jm501436m | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2015-02-13 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Journal of medicinal chemistry | |
pubs.issue | 4 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Tumour Biology & Metastasis | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Tumour Biology & Metastasis | |
pubs.publication-status | Published | |
pubs.volume | 58 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Medicinal Chemistry 1 | |
icr.researchteam | Signal Transduction & Molecular Pharmacology | |
icr.researchteam | Tumour Biology & Metastasis | |
dc.contributor.icrauthor | Workman, Paul | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Clarke, Paul | |
dc.contributor.icrauthor | Eccles, Suzanne | |