Novel CKIα Inhibitors Control Acute Myeloid Leukemia In Preclinical Models

Acute myeloid leukemia (AML) is a malignant disorder with very poor prognosis. In the past decades, there was only little advance in standard therapy for this disease and new therapies are highly needed. Although p53 is usually non-mutated in AML, it is many times inactivated due to impaired regulation. We and others have shown that knockout of casein kinase I α (CKIα) in various models can promote p53 stabilization, suggesting a therapeutic potential for AML. To test this hypothesis, we have recently developed specific CKIα inhibitors and tested them in several AML animal models. First, in the AML model driven by MLL-AF9 translocation, upon inhibitor treatment we observed extended life span and an irreversibly cure of 40% of otherwise lethal disease. Also, in the Tet2^-/-; Flt3^ITD-driven model, a CKIα inhibitor ameliorated the disease profoundly, similarly or better than the FDA approved Flt3-multikinase inhibitor Midostaurin. In these two models, with a single dose of a CKIα inhibitor, there was an acute anti-leukemic effect consisting of a decrease in the number of the blast cells in both bone marrow and peripheral blood, as well as a reduction in spleen mass due to leukemia apoptosis. Robust DDR, p53 and cleaved caspase 3 activation contributed to the acute anti-leukemic effect. Lastly, in a patient-derived AML xenograft model, the leukemia was well controlled by the CKIα inhibitor. The therapeutic effect was far better than that shown by Cytarabine, the standard chemotherapy drug used in leukemia patients. In summary, the robust therapeutic effects of our CKIα inhibitors in three different animal models, suggests that they might have a high therapeutic potential for the treatment of human AML.