Rationally Designed Potent and Selective CK1α Degraders Exert Antiproliferative Activity Against a Broad Range of Human Cancer Cell Lines

Abstract While the PROTAC approach to targeted protein degradation greatly benefits from rational design, the discovery of molecular glue degraders currently relies on screening strategies. Here, we describe screening of a library containing 3,630 cereblon binders against a panel of 9 patient-derived cancer cell lines. This led to the discovery of SJ7590, a potent degrader of CK1α, IKZF1 and IKZF3 proteins. Through a structure-guided optimization strategy we developed SJ3149, a uniquely potent and selective CK1α degrader. The crystal structure of the CK1α+CRBN+DDB1+SJ3149 quaternary complex provided a rationale for the improved degradation properties via direct contacts between SJ3149 and CK1α. In a panel of 115 human cancer cell lines SJ3149 displayed broad antiproliferative activity. This activity profile, which showed statistically significant correlation with MDM2 inhibitor Nutlin-3a, suggests potential for the development of treatments for hematological cancers, as well as solid tumors.