dc.contributor.author | Pasqua, AE | |
dc.contributor.author | Sharp, SY | |
dc.contributor.author | Chessum, NEA | |
dc.contributor.author | Hayes, A | |
dc.contributor.author | Pellegrino, L | |
dc.contributor.author | Tucker, MJ | |
dc.contributor.author | Miah, A | |
dc.contributor.author | Wilding, B | |
dc.contributor.author | Evans, LE | |
dc.contributor.author | Rye, CS | |
dc.contributor.author | Mok, NY | |
dc.contributor.author | Liu, M | |
dc.contributor.author | Henley, AT | |
dc.contributor.author | Gowan, S | |
dc.contributor.author | De Billy, E | |
dc.contributor.author | Te Poele, R | |
dc.contributor.author | Powers, M | |
dc.contributor.author | Eccles, SA | |
dc.contributor.author | Clarke, PA | |
dc.contributor.author | Raynaud, FI | |
dc.contributor.author | Workman, P | |
dc.contributor.author | Jones, K | |
dc.contributor.author | Cheeseman, MD | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2023-08-04T13:24:04Z | |
dc.date.available | 2023-08-04T13:24:04Z | |
dc.date.issued | 2023-04-27 | |
dc.identifier.citation | Journal of Medicinal Chemistry, 2023, 66 (8), pp. 5907 - 5936 | en_US |
dc.identifier.issn | 0022-2623 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5924 | |
dc.identifier.eissn | 1520-4804 | |
dc.identifier.eissn | 1520-4804 | |
dc.identifier.doi | 10.1021/acs.jmedchem.3c00156 | |
dc.description.abstract | CCT251236 1, a potent chemical probe, was previously developed from a cell-based phenotypic high-throughput screen (HTS) to discover inhibitors of transcription mediated by HSF1, a transcription factor that supports malignancy. Owing to its activity against models of refractory human ovarian cancer, 1 was progressed into lead optimization. The reduction of P-glycoprotein efflux became a focus of early compound optimization; central ring halogen substitution was demonstrated by matched molecular pair analysis to be an effective strategy to mitigate this liability. Further multiparameter optimization led to the design of the clinical candidate, CCT361814/NXP800 22, a potent and orally bioavailable fluorobisamide, which caused tumor regression in a human ovarian adenocarcinoma xenograft model with on-pathway biomarker modulation and a clean in vitro safety profile. Following its favorable dose prediction to human, 22 has now progressed to phase 1 clinical trial as a potential future treatment for refractory ovarian cancer and other malignancies. | |
dc.format | Print-Electronic | |
dc.format.extent | 5907 - 5936 | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | AMER CHEMICAL SOC | en_US |
dc.relation.ispartof | Journal of Medicinal Chemistry | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Humans | |
dc.subject | Female | |
dc.subject | Transcription Factors | |
dc.subject | Ovarian Neoplasms | |
dc.subject | Cell Line, Tumor | |
dc.subject | Antineoplastic Agents | |
dc.title | HSF1 Pathway Inhibitor Clinical Candidate (CCT361814/NXP800) Developed from a Phenotypic Screen as a Potential Treatment for Refractory Ovarian Cancer and Other Malignancies. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-04-27 | |
dc.date.updated | 2023-08-04T13:23:30Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1021/acs.jmedchem.3c00156 | en_US |
rioxxterms.licenseref.startdate | 2023-04-27 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/37017629 | |
pubs.issue | 8 | |
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 3 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1021/acs.jmedchem.3c00156 | |
pubs.volume | 66 | |
icr.researchteam | RNA Bio & Mol Therap | en_US |
icr.researchteam | Clinical Pharma & Trials | en_US |
icr.researchteam | Signal Trans & Mol Pharma | en_US |
icr.researchteam | Medicinal Chemistry 3 | en_US |
dc.contributor.icrauthor | Clarke, Paul | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Workman, Paul | |
dc.contributor.icrauthor | Cheeseman, Matthew | |
icr.provenance | Deposited by Mr Arek Surman on 2023-08-04. Deposit type is initial. No. of files: 1. Files: HSF1 Pathway Inhibitor Clinical Candidate (CCT361814NXP800) Developed from a Phenotypic Screen as a Potential Treatment for .pdf | |