Recent Advances in the Development of Casein Kinase 1 Inhibitors

Background: The casein kinase 1 (CK1) family are involved in regulating many cellular processes including membrane trafficking, DNA damage repair, cytoskeleton dynamics, cytoskeleton maintenance and apoptosis. CK1 isoforms especially CK1δ and CK1ε have emerged as important therapeutic target for severe disorders such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), familial advanced sleep phase syndrome and cancer. Due to the importance of CK1 for the pathogenesis of disorders, there are great interests in the development of CK1 inhibitors. Method: Using SciFinder® as a tool, the publications about the biology of CK1 and the recent developments of CK1 inhibitors were surveyed with an exclusion on those published as patents. Results: This review presents the current state of knowledge on the development of CK1 inhibitors, including both the synthetic small molecular inhibitors that were divided into 7 categories according to structural features, and the natural compounds. An overview of the advancement of CK1 inhibitors was given, with the introduction of various existing CK1 inhibitors, their inhibitory activities, and the structure-activity relationships. Conclusion: Thorough physicochemical characterization and biological investigations, it is possible to understand structureactivity relationship of CK1 inhibitors, which will contribute to better design and discovery of potent and selective CK1 inhibitors as potential agents for severe disorders such as AD, ALS and cancer.

Download Full-text

The low complexity regions in the C-terminus are essential for the subcellular localisation of Leishmania casein kinase 1 but not for its activity

10.1101/2020.02.28.969741 ◽

2020 ◽

Author(s):

Daniel Martel ◽

Stewart Pine ◽

Katharina Bartsch ◽

Joachim Clos ◽

Gerald F. Späth ◽

...

Keyword(s):

Host Cell ◽

Membrane Trafficking ◽

Low Complexity ◽

Casein Kinase ◽

Subcellular Localisation ◽

Casein Kinase 1 ◽

Cellular Processes ◽

C Terminus ◽

Wide Range ◽

Eukaryotic Organisms

AbstractCasein Kinase 1 (CK1) family members are serine/threonine protein kinases ubiquitously expressed in eukaryotic organisms. They are involved in a wide range of important cellular processes, such as membrane trafficking, or vesicular transport in organisms from yeast to humans. Due to its broad spectrum of action, CK1 activity and expression is tightly regulated by a number of mechanisms, including subcellular sequestration. Defects in CK1 regulation, localisation or the introduction of mutations in the CK1 coding sequence are often associated with important diseases such as cancer. Increasing evidence suggest that the manipulation of host cell CK1 signalling pathways by intracellular pathogens, either by exploiting the host CK1 or by exporting the CK1 of the pathogen into the host cell may play an important role in infectious diseases. Leishmania CK1.2 is essential for parasite survival and released into the host cell, playing an important role in host pathogen interactions. Although Leishmania CK1.2 has dual role in the parasite and in the host cell, nothing is known about its parasitic localisation and organelle-specific functions. In this study, we show that CK1.2 is a ubiquitous kinase, which is present in the cytoplasm, associated to the cytoskeleton and localised to various organelles, indicating potential roles in kinetoplast and nuclear segregation, as well as ribosomal processing and motility. Furthermore, using truncated mutants, we show for the first time that the two low complexity regions (LCR) present in the C-terminus of CK1.2 are essential for the subcellular localisation of CK1.2 but not for its kinase activity, whereas the deletion of the N-terminus leads to a dramatic decrease in CK1.2 abundance. In conclusion, our data on the localisation and regulation of Leishmania CK1.2 contribute to increase the knowledge on this essential kinase and get insights into its role in the parasite.

Download Full-text

Targeting Casein Kinase 1 (CK1) in Hematological Cancers

International Journal of Molecular Sciences ◽

10.3390/ijms21239026 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9026

Author(s):

Pavlína Janovská ◽

Emmanuel Normant ◽

Hari Miskin ◽

Vítězslav Bryja

Keyword(s):

Clinical Trials ◽

Therapeutic Potential ◽

Clinical Stage ◽

Casein Kinase ◽

Lymphocytic Leukemia ◽

Casein Kinase 1 ◽

Hematological Cancers ◽

Recent Developments ◽

Wnt Pathways ◽

Canonical Wnt

The casein kinase 1 enzymes (CK1) form a family of serine/threonine kinases with seven CK1 isoforms identified in humans. The most important substrates of CK1 kinases are proteins that act in the regulatory nodes essential for tumorigenesis of hematological malignancies. Among those, the most important are the functions of CK1s in the regulation of Wnt pathways, cell proliferation, apoptosis and autophagy. In this review we summarize the recent developments in the understanding of biology and therapeutic potential of the inhibition of CK1 isoforms in the pathogenesis of chronic lymphocytic leukemia (CLL), other non-Hodgkin lymphomas (NHL), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and multiple myeloma (MM). CK1δ/ε inhibitors block CLL development in preclinical models via inhibition of WNT-5A/ROR1-driven non-canonical Wnt pathway. While no selective CK1 inhibitors have reached clinical stage to date, one dual PI3Kδ and CK1ε inhibitor, umbralisib, is currently in clinical trials for CLL and NHL patients. In MDS, AML and MM, inhibition of CK1α, acting via activation of p53 pathway, showed promising preclinical activities and the first CK1α inhibitor has now entered the clinical trials.

Download Full-text

Interaction of Plasmodium falciparum Casein kinase 1 (PfCK1) with components of host cell protein trafficking machinery

10.1101/617571 ◽

2019 ◽

Author(s):

Mitchell B Batty ◽

Ralf B Schittenhelm ◽

Christian Doerig ◽

Jose Garcia-Bustos

Keyword(s):

Plasmodium Falciparum ◽

Membrane Trafficking ◽

Casein Kinase ◽

Cell Protein ◽

Host Proteins ◽

Extracellular Medium ◽

Casein Kinase 1 ◽

Rbc Membrane ◽

Stage Of Development ◽

Higher Eukaryotes

AbstractDuring infection, the Plasmodium falciparum casein kinase 1 (PfCK1) is secreted to the extracellular medium and appears on the RBC membrane during trophozoite stage of development. We attempted to identify a mechanism that describes the secretion of PfCK1 and its appearance on the RBC membrane and suspected a mechanism involving multiple host proteins may be utilised. Indeed, we found that the host proteins GTPase-activating protein and Vps9 domain-containing protein (GAPVD1) and Sorting nexin 22 (SNX22), which have described functions in membrane trafficking in higher eukaryotes, consistently co-purify with PfCK1 suggesting the parasite utilises trafficking pathways previously thought to be inactive in RBCs. Further, reciprocal immunoprecipitation experiments with GAPVD1 identified parasite proteins suggestive of a recycling pathway hitherto only described in higher eukaryotes to recycle membrane proteins. Thus, we have identified components of a trafficking pathway involving parasite proteins that act in concert with host proteins which we hypothesise coordinate the trafficking of PfCK1 during infection.

Download Full-text

The casein kinase 1 family: participation in multiple cellular processes in eukaryotes

Cellular Signalling ◽

10.1016/j.cellsig.2004.12.011 ◽

2005 ◽

Vol 17 (6) ◽

pp. 675-689 ◽

Cited By ~ 347

Author(s):

Uwe Knippschild ◽

Andreas Gocht ◽

Sonja Wolff ◽

Nadine Huber ◽

Jürgen Löhler ◽

...

Keyword(s):

Casein Kinase ◽

Family Participation ◽

Casein Kinase 1 ◽

Cellular Processes

Download Full-text

Characterisation of Casein Kinase 1.1 inLeishmania donovaniUsing the CRISPR Cas9 Toolkit

BioMed Research International ◽

10.1155/2017/4635605 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 14

Author(s):

Daniel Martel ◽

Tom Beneke ◽

Eva Gluenz ◽

Gerald F. Späth ◽

Najma Rachidi

Keyword(s):

High Throughput ◽

Leishmania Donovani ◽

Gene Deletion ◽

Casein Kinase ◽

Casein Kinase 1 ◽

New Approach ◽

New Era ◽

Cellular Processes ◽

Flagellar Protein ◽

Null Mutants

The recent adaptation of CRISPR Cas9 genome editing toLeishmaniaspp. has opened a new era in decipheringLeishmaniabiology. The method was recently improved using a PCR-based CRISPR Cas9 approach, which eliminated the need for cloning. This new approach, which allows high-throughput gene deletion, was successfully validated inL. mexicanaandL. major. In this study, we validated the toolkit inLeishmania donovanitargeting the flagellar protein PF16, confirming that the tagged protein localizes to the flagellum and that null mutants lose their motility. We then used the technique to characterise CK1.1, a member of the casein kinase 1 family, which is involved in the regulation of many cellular processes. We showed that CK1.1 is a low-abundance protein present in promastigotes and in amastigotes. We demonstrated that CK1.1 is not essential for promastigote and axenic amastigote survival or for axenic amastigote differentiation, although it may have a role during stationary phase. Altogether, our data validate the use of PCR-based CRISPR Cas9 toolkit inL. donovani, which will be crucial for genetic modification of hamster-derived, disease-relevant parasites.

Download Full-text

Skeletal elements of crinoid echinoderms: High-resolution structural and microanalytical results

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100074768 ◽

1983 ◽

Vol 41 ◽

pp. 194-195

Author(s):

D. F. Blake ◽

L. F. Allard ◽

D. R. Peacor

Keyword(s):

High Resolution ◽

Marine Invertebrates ◽

Sea Urchins ◽

Structural Features ◽

Sea Stars ◽

High Resolution Tem ◽

Relationship Of ◽

The Relationship ◽

Insight Into

Echinodermata is a phylum of marine invertebrates which has been extant since Cambrian time (c.a. 500 m.y. before the present). Modern examples of echinoderms include sea urchins, sea stars, and sea lilies (crinoids). The endoskeletons of echinoderms are composed of plates or ossicles (Fig. 1) which are with few exceptions, porous, single crystals of high-magnesian calcite. Despite their single crystal nature, fracture surfaces do not exhibit the near-perfect {10.4} cleavage characteristic of inorganic calcite. This paradoxical mix of biogenic and inorganic features has prompted much recent work on echinoderm skeletal crystallography. Furthermore, fossil echinoderm hard parts comprise a volumetrically significant portion of some marine limestones sequences. The ultrastructural and microchemical characterization of modern skeletal material should lend insight into: 1). The nature of the biogenic processes involved, for example, the relationship of Mg heterogeneity to morphological and structural features in modern echinoderm material, and 2). The nature of the diagenetic changes undergone by their ancient, fossilized counterparts. In this study, high resolution TEM (HRTEM), high voltage TEM (HVTEM), and STEM microanalysis are used to characterize tha ultrastructural and microchemical composition of skeletal elements of the modern crinoid Neocrinus blakei.

Download Full-text