Highly Potent and Selective Inhibitors of CK1 Kinases for the Treatment of Leukaemias, Lymphomas and Solid Tumors

INTRODUCTION:

CLL is a lymphoproliferative malignancy with highly heterogeneous disease course and unclear pathogenesis, it is the most common adult leukaemia in western countries, however it is still considered as incurable, albeit the new treatment options have significantly enhanced patients’ response to therapy.

TECHNOLOGY (INVENTION) DESCRIPTION:

Invention relates to highly potent and selective inhibitors of CK1 kinases for the treatment of leukaemias, 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.

ADVANTAGES OVER EXISTING SOLUTIONS:

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 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 treatment of other CK1-driven malignancies. Selective inhibitors targeting CK1 kinases are currently not available for clinical use. Inhibition of CK1-driven signalling is a novel approach of leukaemia and lymphoma treatment, our inhibitors seem to be highly potent and selective so far

DEVELOPMENT STATUS (STAGE):

Preclinical (in CLL case our preclinical in vivo study shows benefit of CK1 inhibition in the combined treatment).

PUBLICATIONS:

1. Kaucká, M. et al. The planar cell polarity pathway drives pathogenesis of chronic lymphocytic leukemia by the regulation of b-lymphocyte migration. Cancer Res. 73 (2013). 2. Kaucká, M. et al. Asymmetry of VANGL2 in migrating lymphocytes as a tool to monitor activity of the mammalian WNT/planar cell polarity pathway. Cell Commun. Signal. 13 (2015). 3. Janovska, P. et al. Autocrine signaling by Wnt-5a deregulates chemotaxis of leukemic cells and predicts clinical outcome in chronic lymphocytic leukemia. Clin. Cancer Res. 22 (2016). 4. Janovska, P. et al. Casein Kinase 1 is a Therapeutic Target in Chronic Lymphocytic Leukemia Blood 131 (2018)

IP PROTECTION STATUS:

European patent pending (previous patents related to CK1 inhibiton and CLL: EU and Canada EP2882437B1, CA2876908C).

TECHNOLOGY / IP OWNERS :

Masaryk University is the owner of IP.

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