biostudies-literatureUnknown15(10)Nishiguchi GAlex&apos;s Lemonade Stand Foundation for Childhood CancerAmerican Lebanese Syrian Associated CharitiesSt. Jude Children&apos;s Research HospitalThe 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 (<b>4</b>), 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, <i>in vitro</i> ADME data, and <i>in vivo</i> phaACS medicinal chemistry letters1692-1698https://www.ebi.ac.uk/biostudies/studies/S-EPMC11472389biostudies-literatureStructure-Activity Relationship of Potent, Selective, and Orally Bioavailable Molecular Glue Degraders of CK1α.PMC11472389Price JRiching KMNishiguchi GYang LDas SFu XDaniels DLShi ZRankovic ZCaine EAMayasundari ALi YKlco JMAggarwal AMcGowan KMascibroda LGUrh MfalseStructure-Activity Relationship of Potent, Selective, and Orally Bioavailable Molecular Glue Degraders of CK1α.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 (<b>4</b>), 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, <i>in vitro</i> ADME data, and <i>in vivo</i> pha2024-01-01T00:00:00Z2024 Oct2026-06-02T23:13:43.987Z2025-04-04T23:49:45.686ZS-EPMC114723893941153910.1021/acsmedchemlett.4c00250