Molecular Glue Screening Identifies CK1α Degrader With ‘Broad Activity’ Against AML Cell Lines

The CK1α degrader SJ3149 demonstrated broad antiproliferative activity against acute leukemia and solid tumor cell lines, according to a study published in Nature Communications.

Gisele Nishiguchi, Lauren Mascibroda, PhD, and Sarah Young, PhD, of St. Jude Children’s Research Hospital, and colleagues conducted this study because, “although CK1α is a potential target for hematological indications, there are no reported inhibitors nor degraders of this kinase with adequate potency and selectivity to enable preclinical validation studies.”

Lenalidomide is the only drug approved by the US Food and Drug Administration (FDA) known to induce CK1α degradation, according to the study’s authors.

The researchers screened a molecular glue library against a panel of 115 pediatric cancer cell lines and identified SJ7095, which has high cytotoxicity against MOLM-13 cells and potent CRBN-dependent degradation of CK1α, IKZF1 and IKZF3 proteins. Through a structure-informed exploration of structure activity relationship, SJ3149—a selective and potent degrader of CK1α protein in vitro and in vivo—was developed.

Based on a favorable absorption, distribution, metabolism, and excretion (ADME) profile, SJ3149 progressed to pharmacokinetics experiments in CD1 female mice, which showed a rapid plasma clearance upon intravenous administration at 3 mg/kg.

The researchers then conducted a pharmacodynamics study of two intraperitoneal dosing regimens: 50 mg/kg once per day and 50 mg/kg twice per day. While both treatment groups demonstrated significant degradation of CK1α, the 50 mg/kg twice per day regimen produced the lower CK1α protein level.

To understand the degradation properties of SJ3149, the compound was cocrystallized in complex with CK1α, CRBN, and DDB1. According to the resulting crystal structure, the core structure that SJ3149 shares with lenalidomide is accommodated similarly in the hydrophobic pocket of CRBN, including direct interaction with residue E377. Unlike lenalidomide, SJ3149 forms several direct interactions with CK1α.

The study also compared the half maximal inhibitory concentration (IC₅₀) profiles of SJ3149 with 120 other anticancer agents to further investigate the mechanism underlying cell line selectivity. SJ3149 showed statistically significant correlation with the MDM2 inhibitor Nutlin-3a, as they both selectively target TP53 wild-type cell lines.

Overall, “these findings suggest potential utility of selective CK1α degraders for treatment of hematological cancers and solid tumors,” the researchers concluded.

Reference

Nishiguchi G, Mascibroda LG, Young SM, et al. Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines. Nat Commun. 2024. doi.org/10.1038/s41467-024-44698-1