Casein Kinase 1 Alpha (CK1α) protein is a serine/threonine kinase involved in key signaling pathways like Wnt/β-catenin and p53, pivotal in cell proliferation and survival. Its aberrant regulation has been implicated in various cancers, including hematological malignancies and solid tumors. The study’s focus on CK1α degraders stems from its potential as a therapeutic target, a notion supported by the limited efficacy of lenalidomide, a known CK1α degrader, in acute myeloid leukemia (AML) and other cancers. The evolution of cancer treatment has witnessed a paradigm shift with the advent of molecular glue degraders, a novel class of therapeutics altering the landscape of targeted cancer therapy. The recent study led by Dr. Jeffery M. Klco and Professor Zoran Rankovic at St. Jude Children’s Research Hospital, as published in Nature Communications, conducted a study that led to significant advancements in targeted cancer therapy. They focused on developing new compounds known as molecular glue degraders, specifically targeting the CK1α protein. Their research, centered on the cereblon (CRBN) ligands, led to the discovery of SJ7095 and its optimized counterpart, SJ3149, which are potent and selective degraders of the CK1α protein. This editorial delves into the scientific ingenuity behind this discovery and its implications for cancer treatment.
The researchers screened a library of CRBN ligands against a panel of patient-derived cancer cell lines. This screening was designed to identify molecules that could selectively target and degrade specific proteins implicated in cancer. Through this screening process, they discovered SJ7095, a compound that showed potent degradation of CK1α, IKZF1, and IKZF3 proteins. Following the discovery of SJ7095, the team engaged in structure-activity relationship (SAR) exploration. Using structural information, they developed SJ3149, an optimized version of SJ7095, which was a more selective and potent degrader of CK1α. The team determined the structure of SJ3149 in complex with CK1α, CRBN, and DDB1. This structural understanding provided insight into why SJ3149 was a more effective degrader than SJ7095. SJ3149’s efficacy was tested across a panel of 115 cancer cell lines, covering both hematological cancers and solid tumors.
The team found SJ3149 to be a highly effective and selective degrader of the CK1α protein, both in vitro and in vivo. SJ3149 demonstrated broad antiproliferative activity against various cancer cell lines. It was notably effective against cell lines with wild-type TP53, a gene crucial in cell cycle regulation and tumor suppression. The activity profile of SJ3149 showed a significant correlation with the MDM2 inhibitor Nutlin-3a, suggesting its potential in treating cancers that are responsive to p53 pathway activation. The study indicates that selective CK1α degraders like SJ3149 could be useful in treating a range of cancers, including those resistant to other forms of therapy.
Molecular glue degraders, by inducing interactions between E3 ligases and target proteins, result in target proteolysis. This mechanism, although effective, has traditionally relied on screening approaches, limiting the specificity and efficiency of such interventions. The discovery of SJ7095 and SJ3149, however, represents a critical leap forward. The authors identified these compounds through a screening of a library of CRBN ligands against various cancer cell lines, showcasing a novel approach in the identification of molecular glue degraders. The discovery of SJ7095 was a result of a high-throughput screening of CRBN ligands. Further structure-activity relationship (SAR) exploration led to the development of SJ3149, a more potent and selective CK1α degrader. This optimization process was informed by the co-crystal structure of SJ3149 in complex with CK1α + CRBN + DDB1, providing insights into the molecular interactions underlying its enhanced degradation properties. Both SJ7095 and SJ3149 demonstrated broad antiproliferative activity across a range of cancer cell lines. Notably, SJ3149 showed a statistically significant correlation with the MDM2 inhibitor Nutlin-3a, highlighting its potential utility in treating cancers with wild-type TP53. This correlation underscores the importance of p53 pathway activation in the mechanism of action of SJ3149.
The authors’ findings suggest that selective CK1α degraders like SJ3149 could be effective in treating a variety of cancers, including hematological malignancies and solid tumors. This opens up new avenues for targeted cancer therapy, particularly for cancers that are unresponsive to current treatments. Moreover, the approach used in this study could serve as a blueprint for the discovery and optimization of other molecular glue degraders, potentially revolutionizing the field of targeted cancer therapy. In conclusion, the research work of Dr. Klco, Professor Rankovic, and their team at St. Jude Children’s Research Hospital represents a significant stride in the realm of targeted cancer therapy. The discovery and optimization of SJ7095 and SJ3149 as selective CK1α degraders not only offer new hope for cancer patients but also pave the way for future research in molecular glue degraders.
Nishiguchi G, Mascibroda LG, Young SM, Caine EA, Abdelhamed S, Kooijman JJ, Miller DJ, Das S, McGowan K, Mayasundari A, Shi Z, Barajas JM, Hiltenbrand R, Aggarwal A, Chang Y, Mishra V, Narina S, Thomas M, Loughran AJ, Kalathur R, Yu K, Zhou S, Wang X, High AA, Peng J, Pruett-Miller SM, Daniels DL, Urh M, Shelat AA, Mullighan CG, Riching KM, Zaman GJR, Fischer M, Klco JM, Rankovic Z. Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines. Nat Commun. 2024;15(1):482. doi: 10.1038/s41467-024-44698-1.