Structure-Activity Relationship of Potent, Selective, and Orally Bioavailable Molecular Glue Degraders of CK1α.

Autor:	Nishiguchi G; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States., Caine EA; Promega Corporation, 5430 East Cheryl Drive, Madison, Wisconsin 53711, United States., McGowan K; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States., Shi Z; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States., Aggarwal A; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States., Mayasundari A; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States., Price J; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States., Yang L; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States., Li Y; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States., Fu X; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States., Mascibroda LG; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States., Das S; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States., Daniels DL; Foghorn Therapeutics Inc, 500 Technology Square, Suite 700, Cambridge, Massachusetts 02139, United States., Urh M; Promega Corporation, 5430 East Cheryl Drive, Madison, Wisconsin 53711, United States., Klco JM; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States., Riching KM; Promega Corporation, 5430 East Cheryl Drive, Madison, Wisconsin 53711, United States., Rankovic Z; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States.; Center for Protein Degradation, The Institute of Cancer Research, London, 15 Cotswold Road, SuttonSM2 5NG, United Kingdom.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2024 Sep 12; Vol. 15 (10), pp. 1692-1698. Date of Electronic Publication: 2024 Sep 12 (Print Publication: 2024).
DOI:	10.1021/acsmedchemlett.4c00250
Abstrakt:	The original molecular glue degraders (thalidomide, lenalidomide, and pomalidomide) are known to bind to cereblon (CRBN) and alter its surface to induce recruitment, ubiquitination, and degradation of therapeutically valuable neosubstrates (IKZF1, IKZF3, and CK1α). With the aim of understanding and modulating neosubstrate specificity, we recently reported the discovery of SJ3149 ( 4 ), a selective and potent molecular glue degrader of CK1α, that is active in multiple cancer cell lines. Herein, we describe the medicinal chemistry efforts that resulted in the discovery of SJ3149 as well as other potent and selective CK1α degraders. We report kinetic profiling and parameters of CK1α degradation, ternary complex, antiproliferative effects, in vitro ADME data, and in vivo pharmacokinetic studies with demonstrated oral bioavailability. Competing Interests: The authors declare no competing financial interest. (© 2024 American Chemical Society.)
Databáze:	MEDLINE
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