Fighting resistant tumors with best-in-class inhibitors of casein kinase 1 (CK1)

Target: Casein kinase 1 (CK1)

• Serine/threonine kinases
• Isoforms α, γ1, γ2, γ3, δ and ε – different expression levels in different pathogeneses
• Implicated in cancer, AD, sleep disorders, obesity, opioid addiction

Goal: Development of highly potent and selective inhibitors of CK1

The small-molecule inhibitors developed by CasInvent Pharma are designed to target with high selectivity and activity individual isoforms of serine-threonine kinases from the Casein kinase 1 (CK1) family. In our research, we have focused on the isoforms CK1 δ, ε as therapeutic targets for the treatment of resistance in melanoma, TNBC and pancreatic cancer, and CK1 α for the treatment of acute myeloid leukemia (AML), with special focus on venetoclax resistance.

The development of the proprietary CK1 inhibitors is based on our studies.

Melanoma is a malignant neoplasm characterized by the uncontrolled growth of pigment-producing cells. Our investigation into the pathological cell signaling in melanoma has primarily concentrated on the regulators influencing cell migration and the interactions of melanoma cells with their surrounding microenvironment. This microenvironmental interaction often facilitates tumor cell survival, disease advancement, and evasion of therapeutic interventions.

Our findings revealed that selectively targeting CK1 δ and ε kinases in melanoma cells alone effectively impedes the migratory capacity of the malignant cells and disrupts their interactions with the protective microenvironment, leading to a significant delay in disease progression in murine models. Notably, the combination of CK1 inhibition with standard melanoma treatment, such as BRAF inhibitors, yielded enhanced, synergistic effects in vitro and a more robust therapeutic response in vivo in our established animal model of melanoma.

Targeting of the kinase CK1 α has been also recently recognized as an attractive therapeutic strategy for the treatment of AML . Similarly, in the realm of AML biology, this hematologic malignancy is marked by highly heterogeneous disease courses and an unclear pathogenesis. Our exploration of the pathological cell signaling in AML has predominantly focused on regulators governing cell migration and the interactions between leukemic cells and their supportive microenvironment. This microenvironmental support often contributes to the survival of tumor cells, disease progression, and resistance to therapeutic interventions. However, most of the published studies have used small-molecule inhibitors with low potency and poor kinase selectivity. Our recently identified series of molecules contains potent and highly selective inhibitors of CK1 α, with minimal off-target effects at therapeutic doses.