Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines
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Published:2024-01-16
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Nishiguchi Gisele, Mascibroda Lauren G.ORCID, Young Sarah M., Caine Elizabeth A.ORCID, Abdelhamed Sherif, Kooijman Jeffrey J.ORCID, Miller Darcie J., Das Sourav, McGowan Kevin, Mayasundari Anand, Shi Zhe, Barajas Juan M., Hiltenbrand Ryan, Aggarwal Anup, Chang Yunchao, Mishra VibhorORCID, Narina ShilpaORCID, Thomas Melvin, Loughran Allister J.ORCID, Kalathur RaviORCID, Yu KaiwenORCID, Zhou Suiping, Wang XushengORCID, High Anthony A., Peng JunminORCID, Pruett-Miller Shondra M.ORCID, Daniels Danette L.ORCID, Urh MarjetaORCID, Shelat Anang A.ORCID, Mullighan Charles G.ORCID, Riching Kristin M.ORCID, Zaman Guido J. R., Fischer MarcusORCID, Klco Jeffery M.ORCID, Rankovic ZoranORCID
Abstract
AbstractMolecular-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.
Funder
Alex’s Lemonade Stand Foundation for Childhood Cancer U.S. Department of Health & Human Services | NIH | National Cancer Institute
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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