CK1 functions
Protein phosphorylation mediated by protein kinases is essential for the activation and deactivation of many signaling pathways in cells. As a result, abnormal protein kinase activity is frequently linked to the onset and progression of multiple diseases, particularly cancer. Accordingly, protein kinases have become one of the most appealing drug inhibition targets, with over 70 small-molecule kinase inhibitors approved for clinical use.
In the early 1970s, in vitro casein phosphorylation experiments revealed that the casein kinase 1 (CK1) family contained multiple members, and numerous substrate combinations of CK1 with various signaling molecules were discovered. Members of the CK1 family can be found in a variety of species. Many eukaryotes, including yeast and humans, express CK1 family members, which are highly conserved. The mammalian CK1 isotypes (α，β，γ，δ，ε) and their splicing variants are involved in a large number of physiological processes such as membrane transport, circadian rhythm, cell cycle regulation, chromosome segregation, apoptosis, and cell differentiation. The non-catalytic domains at the N- and C-termini of all CK1 members differ significantly. Their kinase domains, however, are highly conserved.
In addition to regulating other life processes, CK1’s own activities and expression are strictly regulated to ensure the orderly progression of various life activities. Phosphorylation by inhibitory autophosphorylation or phosphorylation by other cellular protein kinases, interaction with cellular proteins, and subcellular isolation are all known mechanisms for CK1 regulation.
The CK1 family contains binding sites for a wide range of substrates and is involved in the regulation of cellular life processes. It is essential for the regulation of signaling pathways such as Wnt and Hedgehog (Hh), as well as the regulation of circadian rhythm, membrane transport, cytoskeleton maintenance, cell division, DNA repair, and nuclear localization.
The CK1 recognition motif can be identified in a broad spectrum of cells. CK1 regulates different signaling pathways in different forms in the immune inflammatory response and centrosome-related processes, DNA damage-related signal transduction, and circadian rhythm regulation, thereby regulating tissue cell growth, proliferation, apoptosis, and other processes. The dysfunction or disorder of a link in the CK1 family’s signaling pathway will result in pathological processes in the body, such as tumor formation or neurological diseases.
CK1 signaling pathway
Among the kinases that have emerged in the last decade, casein kinase 1 (CK1) has been recognized as an attractive target for the treatment of a variety of diseases, including cancer. Individual CK1 isoforms show a high degree of structural homology, which makes it challenging to identify isomer-selective inhibitors that involve different biological processes. CK1 kinase plays a key role in several cellular communication cascades. For example, CK1δ/ε members are active in Wnt/β-catenin signaling, while CK1α phosphorylates β-catenin and triggers its degradation, acting as inhibitors of Wnt signaling pathways. It also affects the regulation of the Hedgehog and Hippo signaling pathways.
In the typical Wnt/β-catenin signaling pathway, all CK1 family members are involved. This involvement, however, is quite complex. In the absence of Wnt ligand, CK1α interacts and phosphorylates with axin, adenomatous polyposis coli (APC), and β-catenin (Ser-45), triggering further phosphorylation and subsequent degradation of β-catenin by GSK3β. Therefore, the content of β-catenin in the cytoplasm is very low and the transcription of its downstream target genes is inhibited. When the Wnt ligand is present, GSK3β-mediated β-catenin phosphorylation is inhibited and the β-catenin does not eventually degrade. This process is regulated by CK1α, CK1γ, CK1ε, and CK1δ, resulting in the stable presence of β-catenin in the cytoplasm. Free β-catenin is transported to the nucleus and interacts with coactivators such as TCF/LEF complex to activate the transcription of downstream target genes of Wnt.
Research progress in CK1 inhibitors
At present, only BTX-A51 and BTX-1188 developed by Biotheryx Inc have entered the clinic, and both drugs are CK1α combined with other targets. CK1α is also considered to be an attractive target for the treatment of acute myeloid leukemia (AML). In terms of indications, only Pfizer is developing mental diseases, while other drugs are focused on tumors.
Umbralisib (UKONIQ), the first PI3Kδ/CK1ε inhibitor, was developed by TG Therapeutics and approved by the US FDA in February 2021. Umbralisib was investigated by the US FDA for whether it would increase the risk of patient death. Two clinical trials were suspended on January 27, 2022, which were then withdrawn by the FDA to accelerate approval.
Difficulties and risks
Although CK1 inhibitors have substantial potential as drug targets, developing selective CK1 inhibitors that can be used in vivo remains difficult. Every stage of innovative drug development is a near-death adventure. The subsequent clinical application may still be withdrawn from the market if safety and other problems occur.
As a vital participant in the supply chain, BOC Sciences manufactures multitudinous CK1 inhibitors while performing strict quality management so that downstream researchers would be free from raw material worries and then concentrate on the research itself.
Reference
[1] Attwood, M.M., Fabbro, D.,Sokolov, A.V. et al. Trends in kinase drug discovery: targets, indications and inhibitor design[J]. Nat Rev Drug Discov, 2021, 20, 839-861.
[2] Knippschild U , Marc Krüger, Richter J , et al. The CK1 Family: Contribution to Cellular Stress Response and Its Role in Carcinogenesis[J]. Frontiers in Oncology, 2014, 4(4):96.