German Cancer Research Center

Cancer research at the DKFZ spans a wide range of disciplines from fundamental investigations in molecular and cellular biology to clinical studies with cancer patients. In recent years, the DKFZ has established a Drug Discovery Research Group that seeks to translate the discoveries being made in basic research departments into new cancer therapeutics.

Novel cancer targets are pursued in a portfolio of drug discovery projects which are investigated in a milestone-based process. Typically, such projects begin with rigorous target validation work accompanied by assay development to allow for the screening of small molecule inhibitors.

High throughput screening is conducted at the Chemical Biology Core Facility (CBCF), housed at the European Molecular Biology Laboratory (EMBL). The CBCF has a chemically diverse library of 80.000 small molecules, molecular modelling facilities for docking studies and high-throughput in silico screens, and synthetic chemistry resources.

The DKFZ Drug Discovery Group has an experienced medicinal chemistry team that optimizes hit compounds into lead structures, and develops chemical biology tools to optimally characterize those substances. The Drug Discovery Group then evaluates these inhibitors in advanced cellular assays, with the aim to demonstrate proof of concept studies in animal models.

Licensing and commercialization of successful projects is facilitated through a strategic collaboration with Bayer Healthcare.

Publications

Senyilmaz D., Virtue S., Xu X., Tan C.Y., Griffin J.L., Miller A.K., Vidal-Puig A. and Teleman A.A. Regulation of mitochondrial morphology and function by Stearoylation of TfR1. Nature (2015) [In Press].

Zacherl S., La Venuta G., Müller H., Wegehingel S., Dimou E., Sehr P., Lewis J.D., Erfle H., Pepperkok R., Nickel W. A Direct Role for ATP1A1 in Unconventional Secretion of Fibroblast Growth Factor 2. J. Biol. Chem. (2015) 290: 3654.

Pusch, S., Schweizer, L., Beck, A.C., Lehmler, J.M., Weissert, S., Balss, J., Miller, A.K., and von Deimling, A. D-2-Hydroxyglutarate producing neo-enzymatic activity inversely correlates with frequency of the type of isocitrate dehydrogenase 1 mutations found in glioma. Acta Neuropathol. Commun. (2014) 2: 19.

Klika, K.D., Schüler, P., Miller, A.K. The C6 configuration and syn/anti conformational preference of the bisulfite adducts of deoxyuridine and deoxycytidine by NMR and DFT calculations. Tetrahedron: Asymmetry (2014) 25: 20.

Schumacher, T., Bunse, L., Pusch, S., Sahm, F., Wiestler, B., Quandt, J., Menn, O., Osswald, M., Oezen, I., Ott, M., et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature (2014) 512: 324.

Eder, M., Neels, O., Muller, M., Bauder-Wust, U., Remde, Y., Schafer, M., Hennrich, U., Eisenhut, M., Afshar-Oromieh, A., Haberkorn, U., et al. Novel Preclinical and Radiopharmaceutical Aspects of [68Ga]Ga-PSMA-HBED-CC: A New PET Tracer for Imaging of Prostate Cancer. Pharmaceuticals (2014) 7: 779.

Bhuvanagiri M., Lewis J., Putzker K., Becker J.P., Leicht S., Krijgsveld J., Batra R., Turnwald B., Jovanovic B., Hauer C., Sieber J., Hentze M.W., Kulozik A. 5-azacytidine inhibits nonsense-mediated decay in a MYC Dependent Fashion. EMBO Mol. Med. (2014) 6:1593.

Oehme, I., Linke, J.P., Bock, B.C., Milde, T., Lodrini, M., Hartenstein, B., Wiegand, I., Eckert, C., Roth, W., Kool, M., et al. Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc. Natl. Sci. Acad. USA (2013) 110: E2592.

Pautus S., Sehr P., Lewis J., Fortuné A., Wolkerstorfer A., Szolar O., Guilligay D., Lunardi T., Décout J.L., Cusack S. New 7-methylguanine derivatives targeting the influenza polymerase PB2 cap-binding domain. J. Med Chem. (2013) 56: 8915.

Raab, M.S., Breitkreutz, I., Anderhub, S., Ronnest, M.H., Leber, B., Larsen, T.O., Weiz, L., Konotop, G., Hayden, P.J., Podar, K., et al. GF-15, a novel inhibitor of centrosomal clustering, suppresses tumor cell growth in vitro and in vivo. Cancer research (2012) 72: 5374.

Garcia Boy R., Siedlecki P., Musch T., Kliem H.C., Zielenkiewicz P., Suhai S., Wiessler M., Lyko F. Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer Res. (2005) 65: 6305-6311.

Fas S.C., Baumann S., Zhu J.Y., Giaisi M., Treiber M.K., Mahlknecht U., Krammer P.H., Li-Weber M. Wogonin sensitizes resistant malignant cells to TNFalpha- and TRAIL-induced apoptosis. Blood. (2006) 108: 3700-3706.

Friebolin W., Schilling G., Zöller M., Amtmann E. Antitumoral activity of non-platinum xanthate complexes. J. Med. Chem. (2005) 48: 7925-7931.

Miller A.K., Hughes C.C., Kennedy-Smith J.J., Gradl S.N., Trauner D. Total synthesis of (-)-heptemerone B and (-)-guanacastepene E. J. Am. Chem. Soc. (2006) 128: 17057-17062.

Miller A.K., Trauner D. Mining the tetraene manifold: total synthesis of complex pyrones from Placobranchus ocellatus. Angew. Chem. Int. Ed. Engl. (2005) 44: 4602-4606.

Hose, D., Reme, T.,Meissner, T., Moreaux, J., Seckinger, A., Lewis, J., Benes, V., Benner, A., Hundemer, M., Hielscher, T., Shaughnessy, J. D., Jr., Barlogie, B., Neben, K., Kramer, A., Hillengass, J., Bertsch, U., Jauch, A., De Vos, J., Rossi, J. F., Mohler, T., Blake, J., Zimmermann, J., Klein, B., Goldschmidt, H. Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma. Blood. (2009) 113: 4331-4340.

Bartonova, V., Igonet, S., Sticht, J., Glass, B., Habermann, A., Vaney, M. C., Sehr, P., Lewis, J., Rey, F. A., Krausslich, H. G. Residues in the HIV-1 capsid assembly inhibitor binding site are essential for maintaining the assembly-competent quaternary structure of the capsid protein. J. Biol. Chem. (2008) 283: 32024-32033.

Guilligay, D., Tarendeau, F., Resa-Infante, P., Coloma, R., Crepin, T., Sehr, P., Lewis, J., Ruigrok, R. W., Ortin, J., Hart, D. J. Cusack, S. The structural basis for cap binding by influenza virus polymerase subunit PB2. Nat. Struct. Mol. Biol. (2008) 15: 500-506.

Polycarpou-Schwarz, M., Muller, K., Denger, S., Riddell, A., Lewis, J., Gannon, F., Reid, G. Thanatop: a novel 5-nitrofuran that is a highly active, cell-permeable inhibitor of topoisomerase II. Cancer Res. (2007) 67: 4451-4458.

Contact

  • Dr. Aubry Miller

    Cancer Drug Development Group Leader

    German Cancer Research Center

    Im Neuenheimer Feld 580
    69120 Heidelberg
    Germany

    Phone: +49 6221 42-3307
    Fax: +49 6221 42-3318
    E-Mail: Contact

  • Dr. Dirk Kuck

    Project Manager Helmholtz Drug Research

    German Cancer Research Center

    Im Neuenheimer Feld 580
    69120 Heidelberg
    Germany

    Phone: +49 6221 42-2945
    Fax: +49 6221 42-2956
    E-Mail: Contact