dc.contributor.author | Nishiguchi, G | |
dc.contributor.author | Mascibroda, LG | |
dc.contributor.author | Young, SM | |
dc.contributor.author | Caine, EA | |
dc.contributor.author | Abdelhamed, S | |
dc.contributor.author | Kooijman, JJ | |
dc.contributor.author | Miller, DJ | |
dc.contributor.author | Das, S | |
dc.contributor.author | McGowan, K | |
dc.contributor.author | Mayasundari, A | |
dc.contributor.author | Shi, Z | |
dc.contributor.author | Barajas, JM | |
dc.contributor.author | Hiltenbrand, R | |
dc.contributor.author | Aggarwal, A | |
dc.contributor.author | Chang, Y | |
dc.contributor.author | Mishra, V | |
dc.contributor.author | Narina, S | |
dc.contributor.author | Thomas, M | |
dc.contributor.author | Loughran, AJ | |
dc.contributor.author | Kalathur, R | |
dc.contributor.author | Yu, K | |
dc.contributor.author | Zhou, S | |
dc.contributor.author | Wang, X | |
dc.contributor.author | High, AA | |
dc.contributor.author | Peng, J | |
dc.contributor.author | Pruett-Miller, SM | |
dc.contributor.author | Daniels, DL | |
dc.contributor.author | Urh, M | |
dc.contributor.author | Shelat, AA | |
dc.contributor.author | Mullighan, CG | |
dc.contributor.author | Riching, KM | |
dc.contributor.author | Zaman, GJR | |
dc.contributor.author | Fischer, M | |
dc.contributor.author | Klco, JM | |
dc.contributor.author | Rankovic, Z | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2024-07-03T14:25:50Z | |
dc.date.available | 2024-07-03T14:25:50Z | |
dc.date.issued | 2024-01-16 | |
dc.identifier | ARTN 482 | |
dc.identifier | 10.1038/s41467-024-44698-1 | |
dc.identifier.citation | Nature Communications, 2024, 15 (1), pp. 482 - | en_US |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6294 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.doi | 10.1038/s41467-024-44698-1 | |
dc.identifier.doi | 10.1038/s41467-024-44698-1 | |
dc.description.abstract | Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and a target protein, resulting in the target proteolysis. The discovery of molecular glue degraders currently relies mostly on screening approaches. Here, we describe screening of a library of cereblon (CRBN) ligands against a panel of patient-derived cancer cell lines, leading to the discovery of SJ7095, a potent degrader of CK1α, IKZF1 and IKZF3 proteins. Through a structure-informed exploration of structure activity relationship (SAR) around this small molecule we develop SJ3149, a selective and potent degrader of CK1α protein in vitro and in vivo. The structure of SJ3149 co-crystalized in complex with CK1α + CRBN + DDB1 provides a rationale for the improved degradation properties of this compound. In a panel of 115 cancer cell lines SJ3149 displays a broad antiproliferative activity profile, which shows statistically significant correlation with MDM2 inhibitor Nutlin-3a. These findings suggest potential utility of selective CK1α degraders for treatment of hematological cancers and solid tumors. | |
dc.format | Electronic | |
dc.format.extent | 482 - | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | NATURE PORTFOLIO | en_US |
dc.relation.ispartof | Nature Communications | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Humans | |
dc.subject | Antineoplastic Agents | |
dc.subject | Cell Line | |
dc.subject | Neoplasms | |
dc.subject | Proteolysis | |
dc.subject | Ubiquitin-Protein Ligases | |
dc.title | Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-12-21 | |
dc.date.updated | 2024-07-03T14:25:13Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1038/s41467-024-44698-1 | en_US |
rioxxterms.licenseref.startdate | 2024-01-16 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/38228616 | |
pubs.issue | 1 | |
pubs.organisational-group | ICR | |
pubs.publication-status | Published online | |
pubs.publisher-url | http://dx.doi.org/10.1038/s41467-024-44698-1 | |
pubs.volume | 15 | |
icr.researchteam | Targeted Protein Degrad | en_US |
dc.contributor.icrauthor | Rankovic, Zoran | |
icr.provenance | Deposited by Mr Arek Surman on 2024-07-03. Deposit type is initial. No. of files: 1. Files: Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines.pdf | |