Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines.

Autor:	Nishiguchi G; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Mascibroda LG; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Young SM; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Caine EA; Promega Corporation, 5430 East Cheryl Drive, Madison, WI, 53711, USA., Abdelhamed S; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Kooijman JJ; Oncolines B.V., Kloosterstraat 9, 5349 AB, Oss, The Netherlands., Miller DJ; Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Das S; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., McGowan K; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Mayasundari A; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Shi Z; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Barajas JM; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Hiltenbrand R; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Aggarwal A; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Chang Y; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Mishra V; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Narina S; Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Thomas M; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Loughran AJ; Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Kalathur R; Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Yu K; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Zhou S; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Wang X; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., High AA; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Peng J; Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Pruett-Miller SM; Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Memphis, TN, 38105, USA., Daniels DL; Promega Corporation, 5430 East Cheryl Drive, Madison, WI, 53711, USA., Urh M; Promega Corporation, 5430 East Cheryl Drive, Madison, WI, 53711, USA., Shelat AA; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Mullighan CG; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Riching KM; Promega Corporation, 5430 East Cheryl Drive, Madison, WI, 53711, USA., Zaman GJR; Oncolines B.V., Kloosterstraat 9, 5349 AB, Oss, The Netherlands., Fischer M; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. marcus.fischer@stjude.org., Klco JM; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. jeffery.klco@stjude.org., Rankovic Z; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. zoran.rankovic@stjude.org.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2024 Jan 16; Vol. 15 (1), pp. 482. Date of Electronic Publication: 2024 Jan 16.
DOI:	10.1038/s41467-024-44698-1
Abstrakt:	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. (© 2024. The Author(s).)
Databáze:	MEDLINE
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