Transcriptional Profiling for the Classification of Novel Natural Product Drugs

Bernhard Korn
RZPD Resourcenzentrum für Genomforschung
INF 506
69120 Heidelberg, Germany
telephone: +49 (0)6221 42 4700
fax: +49 (0)6221 42 4704
email: b.korn@dkfz.de
prestype: Platform
presenter: Bernhard Korn

Korn, B.1, Gernold, N.1, Seranski, P.2, Möckel, B.2, Eck, J. 2, Zinke, H. 2, Poustka, A.3

1RZPD Resourcenzentrum für Genomforschung , INF 506, 69120 Heidelberg, Germany
2B·R·A·I·N GmbH, 64673 Zwingenberg, Germany
3DKFZ, Molecular Genome Analysis, 69120 Heidelberg, Germany

With the growing number of functionally characterised genes and proteins, the identification of novel pharmaceutical compounds can be supported by the use of transcriptional profiling of already known genes, gene clusters and complex pathways. The specific aim of our work was the identification and functional characterisation of novel compounds from natural product libraries. These compounds are analysed for their activity using cell assays and the functional classification is assigned by the application of array based transcriptional profiling with known cDNAs.

A focus in our drug discovery program lies in the field of oncology and immunomodulation. Therefore, we are using a target oriented cDNA array systems (RZPD onco array) that allows the identification of transcriptional changes in various intra- and intercellular signal transduction pathways leading e.g. to apoptosis, cell-cycle regulation or cytokine production. Unknown products can be classified by comparison of transcriptonal profiles of already known, cytotoxic, cytostatic or antibiotic drugs with arrays from surrogate hosts treated with compounds to be investigated.

We set up an array based classification system for the molecular characterization of recombinant mistletoe lectin, rViscumin, a plant derived ribosome inactivating protein [1,2]. rViscumin is a potent apoptosis inducing drug [3] with immunomodulatory activity in vitro. This drug was applied on the monocytic THP-1 cell line and compared to the expression profile changes induced by other well characterised drugs, e.g. taxol. In response to rViscumin treatment signal transduction pathways were induced, showing that the MAPKinases SAPK/JNK and p38 are activated and transcription factors are induced which regulate gene expression, e.g. cytokine genes. The accumulated data help to understand the molecular mechanism of rViscumin activity and furthermore lead to the identification of predictor gene classes that are subsequently used for screening and characterisation of new drugs.

References

[1] Eck, J. et al.(1999) Eur. J. Biochem. 264, 775-784
[2] Eck, J. et al. (1999) Eur. J. Biochem. 265, 788-797
[3] Möckel, B. et al. (1999) Canc.Res.Clin.Oncol. Suppl. 125, 55-4



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