Inhibitors for the treatment of leukemias, lymphomas and solid tumors | Technology Transfer Office of Masaryk University

Highly Potent and Selective Inhibitors of CK1 Kinases

Field: Novel drugs

Challenge:

B-cell chronic lymphocytic leukemia (CLL) is a lymphoproliferative malignancy with a highly heterogeneous disease course and unclear pathogenesis. CLL is the most common adult leukemia in western countries, however, it is still considered incurable, despite extensive effort invested in the development of novel therapeutic strategies. CLL is characterized by a monoclonal expansion of dysfunctional mature B-lymphocytes that accumulate in both peripheral blood and lymphatic organs, which results in clinical complications such as hypertrophy of organs, reduced function of the immune system, anemia, and others. It is believed that the disease evolves as a result of defects in apoptosis and cell signaling pathways which orchestrate the interaction of the leukemic cells with their supporting microenvironment and regulate cell migration. The migration of leukemic cells to proliferative centers in lymphatic organs is a key process of disease pathogenesis, because it enables the interaction of the leukemic cells with their immediate environment (micro-environment). This interaction then leads to the uncontrolled proliferation of tumor cells and is responsible for the clinical progression of the disease. The protective tumor micro-environment also helps the leukemic cells to survive and evolve and contributes to the development of tumor resistance to therapy.

Currently, no curative therapeutic strategy exists for CLL patients, which are typically treated when they develop an aggressive form of the disease with clinical symptoms. The standard treatment is a combination of chemo- and immuno-therapy (such as FCR; fludarabine+cyclophosphamide and rituximab, which is a monoclonal antibody against surface receptor of B-lymphocytes) and, more recently, also novel inhibitors targeting pro-survival B cell receptor (BCR) or anti-apoptotic B-cell lymphoma 2 (BCL2) signaling, which are in different phases of clinical testing or already approved for use in various patient subgroups. Despite the fact that new treatment options have significantly enhanced patients’ response to therapy, additional improvements are needed in order to prevent relapse of the disease and/or emergence of resistance. This creates a real need for new therapeutic agents which could target the disease more efficiently, with lower side effects and burden for the treated patients and/or act in combination with current therapeutic strategies to achieve final eradication of the disease.

Tech overview:

The development of the proprietary CK1 inhibitors is based on Masaryk University studies of CLL biology. This research of pathological cell signaling in CLL has been focused on regulators of cell migration and interaction of the leukemic cells with their protective microenvironment, which often enables the survival of tumor cells, disease progression, and therapy evasion. Masaryk researchers discovered that targeting of CK1 δ and ε kinases alone in CLL cells is sufficient to block the leukemic cell migration and the microenvironmental interactions and delay the disease progression in mice. Importantly, when combined with standard CLL treatment (ibrutinib, potent inhibitor of B cell receptor signaling), CK1 inhibition provided the benefit of stronger, synergistic effects in vitro and stronger response to therapy in vivo in the used animal model of CLL.

Targeting the kinase CK1 α has been also recently recognized as an attractive therapeutic strategy for the treatment of AML and myelodysplastic syndrome (MDS). However, most of the published studies have used small-molecule inhibitors with low potency and poor kinase selectivity. This recently identified series of molecules contains potent and highly selective inhibitors of CK1 α, with minimal off-target effects at therapeutic doses.

These molecules are designed to target with high selectivity and activity individual isoforms of serine-threonine kinases from the Casein kinase 1 (CK1) family. In this research, the researchers have focused on the isoforms CK1 δ, ε as therapeutic targets for the treatment of chronic lymphocytic leukemia (CLL), and CK1 α for acute myeloid leukemia (AML).

The next research direction is the identification and further development of candidate compounds for the treatment of melanoma. Due to the high financial demands of further research, Masaryk University has established a spin-off company, Casinvent Pharma, whose goal is to bring the best compound with anti-cancer properties to advanced stages of preclinical development.

Benefits:

novel family of potent and selective CK1 inhibitors
selective inhibitors targeting CK1 kinases are currently NOT available for clinical use
unique, versatile, and IP-protected pharmacophore
exceptional selectivity profile, the possibility of targeting specific isoforms, single-digit nM IC₅₀

Applications:

Leukemias represent a group of malignant disorders, characterised by the increased numbers of leucocytes in the blood and/or bone marrow. In 2018, there were in total 437 000 new cases of leukemia and 309 000 leukemia-related deaths worldwide.

The incidence of chronic lymphocytic leukemia (CLL) has increased more than twice in the period of 1990-2017. The global market is predicted to reach 12B USD in 2027, compared to 7.7B USD in 2017. The global market of AML in 2029 is estimated to increase to 5.1B USD, compared to 1.45B USD in 2019. The global melanoma drugs market is estimated to be USD 7.4 billion in 2029.

Commercial opportunity:

The small-molecule inhibitors developed by Masaryk University are at present exclusively licensed to CasInvent Pharma, an early-stage drug discovery spin-off company, which is engaged in the further development of these drugs. Casinvent Pharma has already successfully attracted €1.3 million in investment from private investors and €600,000 in public grant funding. We are currently looking for other investment partners to fund further development.