An Orally Available Derivative of a Specific CK2 Inhibitor for Regulating Circadian Rhythms and Acute Myeloid Leukemia.

The protein kinase CK2 controls cell cycle, apoptosis, and circadian rhythms. The CK2 inhibitor CX-4945 is in clinical trials for cancer treatment, but it has many off-target proteins. Therefore, the development of a bioavailable and specific CK2 inhibitor has been awaited. We previously discovered a specific CK2 inhibitor, GO289, from cell-based phenotypic screening of circadian clock modulators. However, the low water solubility and metabolic stability of GO289 have limited in vivo applications. Here, we developed GO289 derivatives with higher water solubility and metabolic stability. A derivative, GO847, changed the period length of cellular circadian rhythms similar to GO289 and inhibited the growth of acute myeloid leukemia (AML) cells. A proteomic profiling suggested the effects of GO847 and GO289 on pathways related to mitochondrial function, in addition to well-known CK2 targets: cell cycle, apoptosis, RNA metabolism, and protein synthesis. Consistent with this observation, both compounds impaired the metabolic flexibility of mitochondria in AML cells. After oral administration to mice, GO847 was detected in the plasma, liver, spleen, and bone marrow but not in the brain. Together, the findings show that GO847 is a promising candidate for targeting AML, a malignant blood cancer that requires effective treatment.