Multi-Kinase Inhibitors Targeting CKIα and CDK7/9 are Novel Anti Leukemic Compounds with a Strong Immuno-Modulating Activity

Casein Kinase 1 alpha (CKIα) is a major regulator of cellular proliferation. It destabilizes β-catenin and p53 and its ablation hyperactivates the Wnt and p53 pathways. As CKIα affects hematopoietic stem cell survival, we set to explore the effect of CKIα on leukemic stem cells (LSCs). We developed a series of kinase inhibitors that target CKIα and activate p53 and showed that these compounds are highly active against leukemic cells, including LSCs which are generally more resistant to treatment. Further studies showed that these compounds target also CDK7/9, allowing for a robust anti-leukemic response with high specificity. Long term treatment of leukemic mice (MLL-AF9 model) with a selected compound showed prolonged survival and probably cure for 40-50% of the treated mice. Our data further suggests that to achieve long lasting protection and cure, mice need a complete immune system, as Rag1^-/- mice fail to show such protection upon treatment with our lead compound A51. Ongoing studies suggest that T cells are involved in this protection and the cellular mechanisms underlying this protection are being actively explored. Finally, we are able to show that transplanted splenocytes from successfully-treated, likely cured mice in combination with A51 treatment, can confer long term protection to Rag1^-/- mice, suggesting the presence of leukemia specific memory T cells in the rescued mice. As our lead compound A51 is currently moving into clinical trials, understanding the immune regulation exerted by A51 can allow for further combinations with other drugs, to optimize the anti-leukemic effect of our compound.