Structure–Activity\nRelationship of Potent,\nSelective, and Orally Bioavailable Molecular Glue Degraders of CK1α

The original molecular glue degraders (thalidomide, lenalidomide,\nand pomalidomide) are known to bind to cereblon (CRBN) and alter its\nsurface to induce recruitment, ubiquitination, and degradation of\ntherapeutically valuable neosubstrates (IKZF1, IKZF3, and CK1α).\nWith the aim of understanding and modulating neosubstrate specificity,\nwe recently reported the discovery of SJ3149 (<b>4</b>), a selective\nand potent molecular glue degrader of CK1α, that is active in\nmultiple cancer cell lines. Herein, we describe the medicinal chemistry\nefforts that resulted in the discovery of SJ3149 as well as other\npotent and selective CK1α degraders. We report kinetic profiling\nand parameters of CK1α degradation, ternary complex, antiproliferative\neffects, <i>in vitro</i> ADME data, and <i>in vivo</i> pharmacokinetic studies with demonstrated oral bioavailability.