Finally considering the encouraging inhibitory and selectivi
Finally, considering the encouraging inhibitory and selectivity properties of compound and against isolated CK1δ, we have also acquired a very preliminary cytotoxicity profile on human ovarian carcinoma cell line (2008) and on its cisplatin-resistant clone (C13). Results showed that after 48h of exposure to compound IC values were 14.4 and 87.9μM in 2008 and C13 cells, respectively (±95% confidence interval from three different experiments). Interestingly, compound was slightly more potent on the cisplatin resistant cell line (IC 8.0μM) than in cisplatin sensitive cancer Bestatin (IC 122.4μM) (see also ). Considering the wealth of kinase and non-kinase mediate biological activities of anthraquinones, further investigations are in progress to clarify in detail the cytotoxicity pathway(s) activated and regulated in different human tumor cell lines.
Concluding, we have demonstrated the usefulness of our structure-based virtual screening (SBVS) approach to identify novel CK1δ inhibitors. In particular, two amino-anthraquinone analogs (derivatives and ) have demonstrated being among the most potent and selective CK1δ inhibitors known today (IC=0.3 and 0.6μM, respectively). Indeed, we have conformed that anthraquinone scaffold is a versatile scaffold to design specific protein kinase inhibitors, as already reported for other classes of kinases such as for the protein kinase CK2, for the Janus-activated kinase 2 (Jak2), for the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), and the serum and glucocorticoid-inducible kinase (SGK)., An ongoing project is now running in our laboratories to clearly understand the mechanism of action of this new class of promising CK1δ inhibitors with the aim to design and synthesize a second generation of more potent and selective anthraquinone-driven CK1δ inhibitors.
Introduction Protein kinase casein kinase 1 (CK1) belongs to the serine/threonine kinase superfamily that functions as a regulator of signal transduction pathways in most eukaryotic cell types . CK1 isoforms, which are highly conserved in their kinase domains (53%–98% identical) but significantly differ in their regulatory C-terminal region, are involved in Wnt signaling, circadian rhythms, nucleo-cytoplasmic shuttling of transcription factors, DNA repair, and DNA transcription , , . Aberrant functional regulation of CK1, such as its over-expression or excessive activation, has been demonstrated to be implicated in the pathogenesis of many diseases including Alzheimer\'s disease , Parkinson\'s disease , sleep disorders , inflammation  and cancers . Thus CK1 inhibitors have been thought as promising interfering agents in the treatment and prevention of these diseases. Due to the potential application of CK1 inhibitors in various diseases, the development of CK1 inhibitors have attracted much attention in recent years. Though some CK1 inhibitors have been reported, there is no CK1 inhibitor in clinical studies so far. Thus, discovering more potent CK1 inhibitors is still needed, which could provide more lead candidates for drug development. Formerly, the discovery of CK1 inhibitors was achieved through high-throughput screening (HTS)  and subsequent experience-based structural optimization, which usually suffered a high cost and a low success rate. Currently, the fast developing computer-aided drug discovery methods, including virtual screening , , ,  and quantitative structure–activity relationship (QSAR)-guided structural optimization , , , provide economic and rapid approaches to the lead discovery. In this investigation, we shall describe the discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors, which were obtained through virtual screening based on a common-feature pharmacophore model of CK1 inhibitors, and subsequent pharmacophore model guided hit-to-lead optimization.