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Identification of Ellagic acid analogues as potent inhibitor of protein Kinase CK2:A chemopreventive role in oral Cancer.

ABSTRACT: Over expression of Protein kinase (CK2) suppresses apoptosis induced by a variety of agents, whereas down-regulation of CK2 sensitizes cells to induction of apoptosis. In this study, we have built quantitative structure activity relationship (QSAR) models, which were trained and tested on experimentally verified 38 enzyme?s inhibitors having inhibitory value IC50 in µM. These inhibitors were docked at the active site of CK2 (PDB id: 2ZJW) using AutoDock software, which resulted in energy-based descriptors such as binding energy, intermol energy, torsional energy, internal energy and docking energy. For QSAR modeling, Multiple Linear Regression (MLR) model was engendered using energy-based descriptors yielding correlation coefficient r(2) of 0.4645. To assess the predictive performance of QSAR models, different cross-validation procedures were adopted. Our results suggests that ligand-receptor binding interactions for CK2 employing QSAR modeling seems to be a promising approach for prediction of IC50 value of a new ligand molecule against CK2.Further, twenty analogues of ellagic acid were docked with CK2 structure. After docking, two compounds CID 46229200 and CID 10003463 had lower docking energy even lower than standard control Ellagic acid with CK2 was selected as potent candidate drugs for Oral cancer. The biological activity of two compounds in terms of IC50 was predicted based on QSAR model, which could be used as a guideline for anticancerous activity of compounds before their synthesis.

SUBMITTER: Srivastava R

PROVIDER: S-EPMC4349935 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Identification of Ellagic acid analogues as potent inhibitor of protein Kinase CK2:A chemopreventive role in oral Cancer.

Srivastava Rashi R Akthar Salman S Sharma Rolee R Mishra Sanjay S

Bioinformation 20150130 1

Over expression of Protein kinase (CK2) suppresses apoptosis induced by a variety of agents, whereas down-regulation of CK2 sensitizes cells to induction of apoptosis. In this study, we have built quantitative structure activity relationship (QSAR) models, which were trained and tested on experimentally verified 38 enzyme׳s inhibitors having inhibitory value IC50 in µM. These inhibitors were docked at the active site of CK2 (PDB id: 2ZJW) using AutoDock software, which resulted in energy-based d ...[more]

PMID: 25780276

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Project description:Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase, is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component. Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148. Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer and PTEN-deficient MES-SA uterine tumor xenografts was demonstrated. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 due to compensatory feedback loops was observed. Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which demonstrates a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human Phase I trial. The PTEN-deficient U87MG glioblastoma cell line was treated for 6 hours with vehicle control (DMSO) or to different concentrations of AT13148 and CCT128930 (0.1uM, 1xGI50 and 3XGI50).

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Identification of Ellagic acid analogues as potent inhibitor of protein Kinase CK2:A chemopreventive role in oral Cancer.

Publications

Identification of Ellagic acid analogues as potent inhibitor of protein Kinase CK2:A chemopreventive role in oral Cancer.

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