dc.contributor.author | Le Bihan, Y-V | |
dc.contributor.author | Lanigan, RM | |
dc.contributor.author | Atrash, B | |
dc.contributor.author | McLaughlin, MG | |
dc.contributor.author | Velupillai, S | |
dc.contributor.author | Malcolm, AG | |
dc.contributor.author | England, KS | |
dc.contributor.author | Ruda, GF | |
dc.contributor.author | Mok, NY | |
dc.contributor.author | Tumber, A | |
dc.contributor.author | Tomlin, K | |
dc.contributor.author | Saville, H | |
dc.contributor.author | Shehu, E | |
dc.contributor.author | McAndrew, C | |
dc.contributor.author | Carmichael, L | |
dc.contributor.author | Bennett, JM | |
dc.contributor.author | Jeganathan, F | |
dc.contributor.author | Eve, P | |
dc.contributor.author | Donovan, A | |
dc.contributor.author | Hayes, A | |
dc.contributor.author | Wood, F | |
dc.contributor.author | Raynaud, FI | |
dc.contributor.author | Fedorov, O | |
dc.contributor.author | Brennan, PE | |
dc.contributor.author | Burke, R | |
dc.contributor.author | van Montfort, RLM | |
dc.contributor.author | Rossanese, OW | |
dc.contributor.author | Blagg, J | |
dc.contributor.author | Bavetsias, V | |
dc.date.accessioned | 2020-06-03T10:03:20Z | |
dc.date.issued | 2019-09-01 | |
dc.identifier.citation | European journal of medicinal chemistry, 2019, 177 pp. 316 - 337 | |
dc.identifier.issn | 0223-5234 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3675 | |
dc.identifier.eissn | 1768-3254 | |
dc.identifier.doi | 10.1016/j.ejmech.2019.05.041 | |
dc.description.abstract | Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences between the histone substrate binding sites in order to improve affinity for the KDM4-subfamily over KDM5-subfamily enzymes. In particular, residues E169 and V313 (KDM4A numbering) were targeted. Additionally, conformational restriction of the flexible pyridopyrimidinone C8-substituent was investigated. These approaches yielded potent and cell-penetrant dual KDM4/5-subfamily inhibitors including 19a (KDM4A and KDM5B Ki = 0.004 and 0.007 μM, respectively). Compound cellular profiling in two orthogonal target engagement assays revealed a significant reduction from biochemical to cell-based activity across multiple analogues; this decrease was shown to be consistent with 2OG competition, and suggests that sub-nanomolar biochemical potency will be required with C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds to achieve sub-micromolar target inhibition in cells. | |
dc.format | Print-Electronic | |
dc.format.extent | 316 - 337 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Humans | |
dc.subject | Pyridines | |
dc.subject | Pyrimidinones | |
dc.subject | Enzyme Inhibitors | |
dc.subject | Crystallography, X-Ray | |
dc.subject | Drug Screening Assays, Antitumor | |
dc.subject | Molecular Structure | |
dc.subject | Protein Binding | |
dc.subject | Structure-Activity Relationship | |
dc.subject | Jumonji Domain-Containing Histone Demethylases | |
dc.subject | Hydrophobic and Hydrophilic Interactions | |
dc.title | C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-05-14 | |
rioxxterms.versionofrecord | 10.1016/j.ejmech.2019.05.041 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | European journal of medicinal chemistry | |
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/Hit Discovery & Structural Design | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Evaluation and Molecular Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Structural Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/19/20 Starting Cohort | |
pubs.publication-status | Published | |
pubs.volume | 177 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Medicinal Chemistry 1 | |
icr.researchteam | Target Evaluation and Molecular Therapeutics | |
icr.researchteam | Hit Discovery & Structural Design | |
dc.contributor.icrauthor | Le Bihan, Yann-Vai | |
dc.contributor.icrauthor | Carmichael, LeAnne | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Burke, Rosemary | |
dc.contributor.icrauthor | Van Montfort, Robert | |
dc.contributor.icrauthor | Rossanese, Olivia | |
dc.contributor.icrauthor | Bavetsias, Vassilios | |