4tw9

Difluoro-dioxolo-benzoimidazol-benzamides as potent inhibitors of CK1delta and epsilon with nanomolar inhibitory activity on cancer cell proliferation

spinqualitylabelsall models 4tw9, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4tw9 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.4Å Ligands: 386, CL, HSJ, NA, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease KC1D_HUMAN Familial advanced sleep-phase syndrome. The disease is caused by mutations affecting the gene represented in this entry. Function KC1D_HUMAN Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. May act as a negative regulator of circadian rhythmicity by phosphorylating PER1 and PER2, leading to retain PER1 in the cytoplasm. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate. Publication Abstract from PubMed Deregulation of CK1 (casein kinase 1) activity can be involved in the development of several pathological disorders and diseases such as cancer. Therefore, research interest in identifying potent CK1-specific inhibitors is still increasing. A previously published potent and selective benzimidazole-derived CK1delta/epsilon-specific inhibitor compound with significant effects on several tumor cell lines was further modified to difluoro-dioxolo-benzoimidazole derivatives displaying remarkable inhibitory effects and increased intracellular availability. In the present study, we identified two heterocyclic molecules as new CK1-specific inhibitor compounds with favorable physicochemical properties and notable selectivity in a kinome-wide screen. Being compared to other CK1 isoforms, these compounds exhibited advanced isoform selectivity toward CK1delta. Moreover, newly designed compounds showed increased growth inhibitory activity in a panel of different tumor cell lines as determined by analyses of cell viability and cell cycle distribution. In summary, presented lead optimization resulted in new highly selective CK1delta-specific small molecule inhibitors with increased biological activity. Difluoro-dioxolo-benzoimidazol-benzamides As Potent Inhibitors of CK1delta and epsilon with Nanomolar Inhibitory Activity on Cancer Cell Proliferation.,Richter J, Bischof J, Zaja M, Kohlhof H, Othersen O, Vitt D, Alscher V, Pospiech I, Garcia-Reyes B, Berg S, Leban J, Knippschild U J Med Chem. 2014 Sep 17. PMID:25191940 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Casein kinase 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA