CasInvent Pharma - Developing highly potent and selective inhibitors of CK1 kinases for the treatment of leukemias, lymphomas and solid tumors
Prof. Vitezslav Bryja, Masaryk University; Prof. Kamil Paruch, Masaryk University; Dr Pavlina Janovska, Masaryk University; Vaclav Nemec, Masaryk University
Masaryk University, TTO
AML has many different forms and subtypes and is associated with severe complications and high mortality. Despite the approval of several novel treatments, the fundamental approach to the treatment of AML has remained constant over 30 years and relies on induction and consolidation chemotherapy, or stem cell transplant. Thus, novel treatments, specifically for older and high-risk patients, are needed. Chronic lymphocytic leukaemia (CLL) and acute myeloid leukaemia (AML) are lymphoproliferative malignancies. CLL is a highly heterogeneous disease with unclear pathogen¬esis. It is the most common adult leukaemia in western countries. However, it is still considered to be incurable, despite extensive efforts invested in the development of novel therapeutic strategies and new treatment options that have significantly enhanced patients’ response to therapy.
The present 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 CLL and AML, the invention presents novel heterocyclic compounds for use in the treatment of leukaemias as well as other cancer types based on similar mechanisms of the disease pathogenesis and common signalling pathways that are disrupted (e.g. breast cancer, melanoma, prostate/pancreatic/ovarian cancer). In a preclinical study, we showed that the targeting of microenvironmental interactions and cell migration via CK1 inhibition can be successfully applied and brings benefits in vivo in a mouse model of CLL. CK1 inhibition combined with currently used treatment improves the survival of mice, which shows the potential for such a therapeutic setting. Similarly, the inhibition of CK1 prolonged the survival and delayed the disease progression in the xenograft model of AML.
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 models in vivo. The primary focus of the research is on CLL and AML, the role of CK1 kinase in CLL pathogenesis was shown previously by our research group (see further reading). The presented invention also has great 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 signalling is a novel approach to leukaemia and lymphoma treatment. Masaryk University has recently established the spin-off company CasInvent Pharma, a.s., which will develop the presented technology until early clinical phases. In case of interest in the collaboration with the company, please contact Dr. Trautmann (contact information below). 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 models in vivo. The primary focus of the research is on CLL and AML and other CK1-driven malignancies. Selective inhibitors targeting CK1 kinases are currently not available for clinical use.
Janovská P. et al. Targeting Casein Kinase 1 (CK1) in Hematological Cancers. Int J Mol Sci. 2020, 21, 9026.
Janovska, P. et al. Casein Kinase 1 is a Therapeutic Target in Chronic Lymphocytic Leukemia. Blood 131, blood-2017-05-786947 (2018)