Expanding the chemical diversity of CK2 inhibitors
- 280 Downloads
None of the already described CK2 inhibitors did fulfill the requirements for successful clinical settings. In order to find innovative CK2 inhibitors based on new scaffolds, we have performed a high-throughput screening of diverse chemical libraries. We report here the identification and characterization of several classes of new inhibitors. Whereas some share characteristics of previously known CK2 inhibitors, others are chemically unrelated and may represent new opportunities for the development of better CK2 inhibitors. By combining structure-activity relationships with a docking procedure, we were able to determine the binding mode of these inhibitors. Interestingly, beside the identification of several nanomolar ATP-competitive inhibitors, one class of chemical inhibitors displays a non-ATP competitive mode of inhibition, a feature that suggests that CK2 possess distinct druggable binding sites. For the most promising inhibitors, selectivity profiling was performed. We also provide evidence that some chemical compounds are inhibiting CK2 in living cells. Finally, the collected data allowed us to draw the rules about the chemical requirements for CK2 inhibition both in vitro and in a cellular context.
KeywordsCK2 Kinase inhibitors Non-competitive
Casein kinase 2
This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Centre National pour la Recherche Scientifique (CNRS), the Commissariat à l’Energie Atomique (CEA), the Institut Curie, the Ligue Nationale Contre le Cancer (équipe labellisée 2007), the Institut National du Cancer (Grant Number 57). The authors thanks the Drug Synthesis & Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI, for the library of low-molecular-weight compounds, the ChemAxon company (http://www.chemaxon.com) for allowing academics to freely use their software, especially here the Standardizer and the Calculator Plugins to compute descriptors and the MarvinView package, for viewing structure files in our home-made software, PhenoScreen.
- 7.Nie Z, Perretta C, Erickson P, Margosiak S, Almassy R, Lu J et al (2007) Structure-based design, synthesis, and study of pyrazolo[1, 5-a][1, 3, 5]triazine derivatives as potent inhibitors of protein kinase CK2. Bioorg Med Chem Lett 17:4191–4195. doi: 10.1016/j.bmcl.2007.05.041 PubMedCrossRefGoogle Scholar
- 9.Duncan JS, Gyenis L, Lenehan J, Bretner M, Graves LM, Haystead TA et al (2008) An unbiased evaluation of CK2 inhibitors by chemo-proteomics: characterization of inhibitor effects on CK2 and identification of novel inhibitor targets. Mol Cell Proteomics; Epub ahead of printGoogle Scholar
- 13.SYBYL, version 6.9; Tripos Inc. (1699 South Hanley Road, St. Louis, MO, 63144)Google Scholar
- 14.FlexX, Version 1.13.5; Sankt Augustin, Germany BioSolveIT GmbHGoogle Scholar
- 17.Gasteiger J, Engel T (2004) Chemoinformatics: a textbook. Wiley. ISBN 3-527-30681-1Google Scholar
- 18.Viswanadhan VN, Ghose AK, Revankar GR, Robins RK (1989) Atomic physicochemical parameters for three dimensional structure directed quantitative structure–activity relationships. 4. Additional parameters for hydrophobic and dispersive interactions and their application for an automated superposition of certain naturally occurring nucleoside antibiotics. J Chem Inf Comput Sci 29:163–172. doi: 10.1021/ci00063a006 Google Scholar
- 23.Eibe F, Witten IH (1998) generating accurate rule sets without global optimization. In: Fifteenth International Conference on Machine Learning, pp 144–151Google Scholar
- 30.Chin PC, Liu L, Morrison BE, Siddiq A, Ratan RR, Bottiglieri T et al (2004) The c-Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK-ERK and Akt-independent mechanism. J Neurochem 90:595–608. doi: 10.1111/j.1471-4159.2004.02530.x PubMedCrossRefGoogle Scholar
- 36.Koceva-Chyla A, Jedrzejczak M, Skierski J, Kania K, Jozwiak Z (2005) Mechanisms of induction of apoptosis by anthraquinone anticancer drugs aclarubicin and mitoxantrone in comparison with doxorubicin: relation to drug cytotoxicity and caspase-3 activation. Apoptosis 10:1497–1514. doi: 10.1007/s10495-005-1540-9 PubMedCrossRefGoogle Scholar
- 39.Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F et al (2007) Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 110:3540–3546. doi: 10.1182/blood-2007-03-080689 PubMedCrossRefGoogle Scholar