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Ck1 delta

Travis T Wager, Paul Galatsis, Ramalakshmi Y Chandrasekaran, Todd W Butler, Jianke Li, Lei Zhang, Scot Mente, Chakrapani Subramanyam, Shenping Liu, Angela C Doran, Cheng Chang, Katherine Fisher, Sarah Grimwood, Joseph R Hedde, Michael Marconi, Klaas Schildknegt
To enable the clinical development of our CNS casein kinase 1 delta/epsilon (CK1δ/ε) inhibitor project, we investigated the possibility of developing a CNS positron emission tomography (PET) radioligand. For this effort, we focused our design and synthesis efforts on the initial CK1δ/ε inhibitor HTS hits with the goal of identifying a compound that would fulfill a set of recommended PET ligand criteria. We identified [(3)H]PF-5236216 (9) as a tool ligand that meets most of the key CNS PET attributes including high CNS MPO PET desirability score and kinase selectivity, CNS penetration, and low nonspecific binding...
June 30, 2017: ACS Chemical Neuroscience
Sonja Wolff, Zhenyu Xiao, Mathias Wittau, Nadine Süssner, Martin Stöter, Uwe Knippschild
No abstract text is available yet for this article.
October 2017: Biochimica et Biophysica Acta
Gracie Wee Ling Eng, Edison, David M Virshup
Circadian rhythms are intrinsic ~24 hour cycles that regulate diverse aspects of physiology, and in turn are regulated by interactions with the external environment. Casein kinase 1 delta (CK1δ, CSNK1D) is a key regulator of the clock, phosphorylating both stabilizing and destabilizing sites on the PER2 protein, in a mechanism known as the phosphoswitch. CK1δ can itself be regulated by phosphorylation on its regulatory domain, but the specific sites involved, and the role this plays in control of circadian rhythms as well as other CK1-dependent processes is not well understood...
2017: PloS One
Jit Kong Cheong, David M Virshup
Aberrant Wnt signaling has been widely accepted to be a key driver of a subset of human cancers and a heavily scrutinized molecular pathway for the development of personalized medicine. In a recently published issue of Science Translational Medicine, Rosenberg and coworkers reported that the delta isoform of the CK1 family of serine/threonine kinases (CK1δ), an important mediator of intracellular Wnt signaling, is amplified and overexpressed in human breast tumors. They further demonstrated that pharmacological inhibition of CK1δ is efficacious for these cancers and implicate β-catenin signaling as a key target of CK1δ...
November 2016: Annals of Translational Medicine
Changchun Deng, Mark R Lipstein, Luigi Scotto, Xavier O Jirau Serrano, Michael A Mangone, Shirong Li, Jeremie Vendome, Yun Hao, Xiaoming Xu, Shi-Xian Deng, Ronald B Realubit, Nicholas P Tatonetti, Charles Karan, Suzanne Lentzsch, David A Fruman, Barry Honig, Donald W Landry, Owen A O'Connor
Phosphoinositide 3-kinase (PI3K) and the proteasome pathway are both involved in activating the mechanistic target of rapamycin (mTOR). Because mTOR signaling is required for initiation of messenger RNA translation, we hypothesized that cotargeting the PI3K and proteasome pathways might synergistically inhibit translation of c-Myc. We found that a novel PI3K δ isoform inhibitor TGR-1202, but not the approved PI3Kδ inhibitor idelalisib, was highly synergistic with the proteasome inhibitor carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary lymphoma and leukemia cells...
January 5, 2017: Blood
Surya Pratap Singh, Dwijendra K Gupta
Wnt signaling pathway regulates several developmental processes in human; however recently this pathway has been associated with development of different types of cancers. Casein kinase-1 (CK1) constitutes a family of serine-threonine protein kinase; various members of this family participate in Wnt signal transduction pathway and serve as molecular switch to this pathway. Among the known six isoforms of CK1, in human, at least three isoforms (viz. alpha, delta and epsilon) have been reported as oncogenic. The development of common therapeutics against these kinases is an arduous task; unless we have the detailed information of their tertiary structures and conformational properties...
April 21, 2015: Journal of Theoretical Biology
Filip Laco, Joo-Leng Low, Jasmin Seow, Tsung Liang Woo, Qixing Zhong, Jayasree Seayad, Zhenfeng Liu, Heiming Wei, Shaul Reuveny, David A Elliott, Christina L L Chai, Steve K W Oh
Differentiation of human pluripotent stem cells as embryoid bodies (EBs) has been achieved previously with p38alfa MAPK inhibitors such as SB203580 with moderate efficiency of 10-15%. We synthesized and screened 42 compounds that are 2,4,5-trisubstituted azole analogues of SB203580 for efficient cardiomyocyte differentiation. Our screen identified novel compounds that have similar cardiac differentiation activity as SB203580. However, the cardiac differentiation did not correlate with p38alfa MAPK inhibition, indicating an alternative mechanism in cardiac differentiation...
March 2015: Journal of Molecular and Cellular Cardiology
Travis T Wager, Ramalakshmi Y Chandrasekaran, Jenifer Bradley, David Rubitski, Helen Berke, Scot Mente, Todd Butler, Angela Doran, Cheng Chang, Katherine Fisher, John Knafels, Shenping Liu, Jeff Ohren, Michael Marconi, George DeMarco, Blossom Sneed, Kevin Walton, David Horton, Amy Rosado, Andy Mead
Casein kinase 1 delta (CK1δ) and casein kinase 1 epsilon (CK1ε) inhibitors are potential therapeutic agents for a range of psychiatric disorders. The feasibility of developing a CNS kinase inhibitor has been limited by an inability to identify safe brain-penetrant compounds with high kinome selectivity. Guided by structure-based drug design, potent and selective CK1δ/ε inhibitors have now been identified that address this gap, through the design and synthesis of novel 4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine derivatives...
December 17, 2014: ACS Chemical Neuroscience
Yoshimi Endo Greer, Christopher J Westlake, Bo Gao, Kapil Bharti, Yoko Shiba, Charles P Xavier, Gregory J Pazour, Yingzi Yang, Jeffrey S Rubin
Inhibition of casein kinase 1 delta (CK1δ) blocks primary ciliogenesis in human telomerase reverse transcriptase immortalized retinal pigmented epithelial and mouse inner medullary collecting duct cells-3. Mouse embryonic fibroblasts (MEFs) and retinal cells from Csnk1d (CK1δ)-null mice also exhibit ciliogenesis defects. CK1δ catalytic activity and centrosomal localization signal (CLS) are required to rescue cilia formation in MEFs(Csnk1d null). Furthermore, expression of a truncated derivative containing the CLS displaces full-length CK1δ from the centrosome and decreases ciliary length in control MEFs, suggesting that centrosomal CK1δ has a role in ciliogenesis...
May 2014: Molecular Biology of the Cell
Shu-Hui Lin, Yueh-Min Lin, Chung-Min Yeh, Chih-Jung Chen, Mei-Wen Chen, Hsiao-Fang Hung, Kun-Tu Yeh, Shun-Fa Yang
Casein kinase 1 is a group of ubiquitous serine/threonine kinases that are involved in normal cellular functions and several pathological conditions, such as DNA repair, cell cycle progression, cytokinesis, differentiation, and apoptosis. Recent studies have indicated that casein kinase 1-epsilon (CK1ε) and casein kinase 1-delta (CK1δ) expression has a role in human cancers. We investigated the associations between CK1ε and CK1δ expression and the clinical parameters of oral cancer using immunohistochemical study methods on oral squamous cell carcinoma specimens...
2014: International Journal of Molecular Sciences
Ambuj Kumar, Vidya Rajendran, Rao Sethumadhavan, Rituraj Purohit
CK1δ (Casein kinase I isoform delta) is a member of CK1 kinase family protein that mediates neurite outgrowth and the function as brain-specific microtubule-associated protein. ATP binding kinase domain of CK1δ is essential for regulating several key cell cycle signal transduction pathways. Mutation in CK1δ protein is reported to cause cancers and affects normal brain development. S97C mutation in kinase domain of CK1δ protein has been involved to induce breast cancer and ductal carcinoma. We performed molecular docking studies to examine the effect of this mutation on its ATP-binding affinity...
2014: Journal of Biomolecular Structure & Dynamics
Sima Smadja Storz, Adi Tovin, Philipp Mracek, Shahar Alon, Nicholas S Foulkes, Yoav Gothilf
Zebrafish have become a popular model for studies of the circadian timing mechanism. Taking advantage of its rapid development of a functional circadian clock and the availability of light-entrainable clock-containing cell lines, much knowledge has been gained about the circadian clock system in this species. However, the post-translational modifications of clock proteins, and in particular the phosphorylation of PER proteins by Casein kinase I delta and epsilon (CK1δ and CK1ε), have so far not been examined in the zebrafish...
2013: PloS One
Hao Chen, Honghui Ma, Hiroyuki Inuzuka, Jianbo Diao, Fei Lan, Yujiang Geno Shi, Wenyi Wei, Yang Shi
UHRF1 (ubiquitin-like, with PHD and RING finger domains 1) is a critical epigenetic player involved in the maintenance of DNA methylation patterns during DNA replication. Dysregulation of the UHRF1 level is implicated in cancer onset, metastasis, and tumor recurrence. Previous studies demonstrated that UHRF1 can be stabilized through USP7-mediated deubiquitylation, but the mechanism through which UHRF1 is ubiquitylated is still unknown. Here we show that proteasomal degradation of UHRF1 is mediated by the SCF(β-TrCP) E3 ligase...
March 2013: Molecular and Cellular Biology
Lorna S Kategaya, Aisha Hilliard, Louying Zhang, John M Asara, Louis J Ptáček, Ying-Hui Fu
Throughout the day, clock proteins synchronize changes in animal physiology (e.g., wakefulness and appetite) with external cues (e.g., daylight and food). In vertebrates, both casein kinase 1 delta and epsilon (CK1δ and CK1ε) regulate these circadian changes by phosphorylating other core clock proteins. In addition, CK1 can regulate circadian-dependent transcription in a non-catalytic manner, however, the mechanism is unknown. Furthermore, the extent of functional redundancy between these closely related kinases is debated...
2012: PloS One
Heidrun Hirner, Cagatay Günes, Joachim Bischof, Sonja Wolff, Arnhild Grothey, Marion Kühl, Franz Oswald, Florian Wegwitz, Michael R Bösl, Anna Trauzold, Doris Henne-Bruns, Christian Peifer, Frank Leithäuser, Wolfgang Deppert, Uwe Knippschild
Simian virus 40 (SV40) is a powerful tool to study cellular transformation in vitro, as well as tumor development and progression in vivo. Various cellular kinases, among them members of the CK1 family, play an important role in modulating the transforming activity of SV40, including the transforming activity of T-Ag, the major transforming protein of SV40, itself. Here we characterized the effects of mutant CK1δ variants with impaired kinase activity on SV40-induced cell transformation in vitro, and on SV40-induced mammary carcinogenesis in vivo in a transgenic/bi-transgenic mouse model...
2012: PloS One
Alexander Long, Huilin Zhao, Xin Huang
Casein kinase 1 delta (CK1δ) and its closest homologue CK1ε are key regulators of diverse cellular growth and survival processes such as Wnt signaling, DNA repair, and circadian rhythms. We report three crystal structures of the kinase domain of human CK1δ, one apo and two complexed with a potent and selective CK1δ/ε inhibitor PF670462 in two different crystal forms. These structures provide a molecular basis for the strong and specific inhibitor interactions and suggest clues for further development of CK1δ/ε inhibitors...
January 26, 2012: Journal of Medicinal Chemistry
Yoshimi Endo Greer, Jeffrey S Rubin
Previously we determined that Dishevelled-2/3 (Dvl) mediate Wnt-3a-dependent neurite outgrowth in Ewing sarcoma family tumor cells. Here we report that neurite extension was associated with Dvl phosphorylation and that both were inhibited by the casein kinase 1 (CK1) δ/ε inhibitor IC261. Small interfering RNAs targeting either CK1δ or CK1ε decreased Dvl phosphorylation, but only knockdown of CK1δ blocked neurite outgrowth. CK1δ but not CK1ε was detected at the centrosome, an organelle associated with neurite formation...
March 21, 2011: Journal of Cell Biology
J K Cheong, T H Nguyen, H Wang, P Tan, P M Voorhoeve, S H Lee, D M Virshup
Casein kinase 1 delta and epsilon (CK1δ/ɛ) are key regulators of diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. Recent studies suggest that they have an important role in oncogenesis. RNA interference screens identified CK1ɛ as a pro-survival factor in cancer cells in vitro and the CK1δ/ɛ-specific inhibitor IC261 is remarkably effective at selective, synthetic lethal killing of cancer cells. The recent development of the nanomolar CK1δ/ɛ-selective inhibitor, PF670462 (PF670) and the CK1ɛ-selective inhibitor PF4800567 (PF480) offers an opportunity to further test the role of CK1δ/ɛ in cancer...
June 2, 2011: Oncogene
Qing-Jun Meng, Elizabeth S Maywood, David A Bechtold, Wei-Qun Lu, Jian Li, Julie E Gibbs, Sandrine M Dupré, Johanna E Chesham, Francis Rajamohan, John Knafels, Blossom Sneed, Laura E Zawadzke, Jeffrey F Ohren, Kevin M Walton, Travis T Wager, Michael H Hastings, Andrew S I Loudon
Circadian pacemaking requires the orderly synthesis, posttranslational modification, and degradation of clock proteins. In mammals, mutations in casein kinase 1 (CK1) epsilon or delta can alter the circadian period, but the particular functions of the WT isoforms within the pacemaker remain unclear. We selectively targeted WT CK1epsilon and CK1delta using pharmacological inhibitors (PF-4800567 and PF-670462, respectively) alongside genetic knockout and knockdown to reveal that CK1 activity is essential to molecular pacemaking...
August 24, 2010: Proceedings of the National Academy of Sciences of the United States of America
Cornelia Rumpf, Lubos Cipak, Andrej Dudas, Zsigmond Benko, Miroslava Pozgajova, Christian G Riedel, Gustav Ammerer, Karl Mechtler, Juraj Gregan
Segregation of chromosomes during meiosis depends on separase cleavage of Rec8, the meiosis-specific alpha-kleisin subunit of cohesin. We mapped Rec8 phosphorylation sites by mass spectrometry and show that Rec8 phosphorylation is required for proper chromosome disjunction during meiosis. We further show that the fission yeast casein kinase 1 (CK1) delta/epsilon isoforms Hhp1 and Hhp2 are required for full levels of Rec8 phosphorylation and for efficient removal of Rec8 at the onset of anaphase I. Our data are consistent with the model that Hhp1/Hhp2-dependent phosphorylation of Rec8 is required for separase-mediated cleavage of Rec8 during meiosis I...
July 1, 2010: Cell Cycle
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