Novel curcumin- and emodin-related compounds identified by in silico 2D/3D conformer screening induce apoptosis in tumor cells

Here we present a novel method to identify efficient inhibitors of CSN-associated kinases. Using curcumin and emodin as lead structures an in silico screening with our in-house database containing more than 106 structures was carried out. Thirty-five compounds were identified and further evaluated by the Lipinski's rule-of-five. Two groups of compounds can be clearly discriminated according to their structures: the curcumin-group and the emodin-group. The compounds were evaluated in in vitro kinase assays and in cell culture experiments.The data revealed 3 compounds of the curcumin-group (e.g. piceatannol) and 4 of the emodin-group (e.g. anthrachinone) as potent inhibitors of CSN-associated kinases. Identified agents increased p53 levels and induced apoptosis in tumor cells as determined by annexin V-FITC binding, DNA fragmentation and caspase activity assays.Our data demonstrate that the new in silico screening method is highly efficient for identifying potential anti-tumor drugs.The COP9 signalosome (CSN), a conserved multimeric protein complex, functions at the interface between signal transduction and ubiquitin (Ub)-dependent proteolysis [1]. Because of associated enzymes, the CSN possesses kinase acitivity. Two of the associated kinases are the protein kinase CK2 (CK2) and the protein kinase D (PKD) [2]. More than 200 proteins are known to be phosphorylated by the CK2, which is located nearly everywhere in the cell. The PKD is a serine/threonine kinase localized at either the plasma membrane or the cytosol of lymphocytes [3] and is associated with very diverse cellular functions, including Golgi organization, plasma membrane directed transport, metastasis, immune response, apoptosis and cell proliferation [4]. It is assumed that the CSN is a platform that brings together the kinases and appropriate substrates [5]. Transcriptional regulators such as p53 and c-Jun are phosphorylated by the CSN kinases [6,7]. The phosphorylation of p53 at Thr155 results in Ub-depe