CLL is a lymphoproliferative malignancy with highly heterogeneous disease course and unclear pathogenesis. It is the most common adult leukemia in western countries. However, it is still considered to be incurable, despite extensive effort invested in the development of novel therapeutic strategies and new treatment options which have significantly enhanced patients' response to therapy.
The present invention relates to highly potent and selective inhibitors of CK1 kinases for the treatment of leukemias, lymphomas, and solid tumors. With the main focus on B-cell chronic lymphocytic leukemia (CLL), the invention presents novel heterocyclic compounds for use in treatment of CLL as well as other cancer types based on similar mechanisms of the disease pathogenesis and common signalling pathways which are disrupted (e.g. breast cancer, melanoma, prostate/pancreatic/ovarian cancer). In a preclinical study, we showed that targeting of microenvironmental interactions and cell migration via CK1 inhibition can be successfully applied in case of CLL and brings benefits in vivo in a mouse model of CLL. CK1 inhibition combined with currently used treatment improves survival of the mice, which shows the potential for such a therapeutic setting.
The novel inhibitors of CK1 kinases have high activity against primary targets and an exceptional selectivity profile in vitro. They are orally bioavailable and well-tolerated at therapeutic doses in a mouse model in vivo. The primary focus of the research is on CLL and lymphomas, the role of CK1 kinase in CLL pathogenesis was shown previously by our research group. However, the invention has a huge potential in the treatment of other CK1-driven malignancies. Selective inhibitors targeting CK1 kinases are currently not available for clinical use. Inhibition of CK1-driven signaling is a novel approach of leukemia and lymphoma treatment, our inhibitors are highly potent and selective. Masaryk University is actively searching for a research partner and partner for out-licensing of the technology. Interested parties are kindly invited to contact the Technology Transfer Office to further explore the possibilities of partnership.
Preclinical (in CLL case our preclinical in vivo study shows the benefit of CK1 inhibition in the combined treatment).
European patent pending (previous patents related to CK1 inhibition and CLL: EU and Canada EP2882437B1, CA2876908C).
Janovska, P. et al. Casein Kinase 1 is a Therapeutic Target in Chronic Lymphocytic Leukemia. Blood 131, blood-2017-05-786947 (2018).