Research

The group is active in four areas of cancer drug discovery: 1)Target Identification and Validation 2) Assay Development and Screening 3) Synthetic Organic Chemistry and 4) Biological Testing. These activities are combined to discover specific inhibitors and to establish candidate drugs for clinical testing.

Target Identification and Validation (Dr. Mona Malz)

To be successful the target validation process needs to allign clinical and mechanistic aspects of cancer with modern drug discovery technology

Apart from unfavorable phys-chem properties, the main reason for insufficient efficacy of new cancer drugs is the use of insufficiently validated targets in the drug discovery process. Target identification usually is an outcome of basic biomedical research. Experimental results indicate that a gene product maybe important in cancer pathology, e.g. knock down causes

  • inhibition of pro-survival signaling pathways;
  • inhibition of cell cycle progression; or
  • enhancement of the cytotoxic effects of anti-cancer agents.

This may then indicate that the gene product could be a potential drug target. Our target validation strategy aims to demonstrate and confirm that the identified target candidate is an essential component of a cancer related process.

General Criteria for  a Validated Drug Target

We don't expect that all the of the critera listed below to be available for a protein to be a good drug target. However, the more the better:

  • Target addresses a clear medical need.
  • Target is shown to have genetic linkage to disease in humans.
  • Validation data: in vitro or in vivo generated data in disease models.
  • Target is of a class known to be "druggable," however, novel drug targets are of great interest.
  • Knowledge of natural ligand or substrate if available to support assay development strategy.
  • Target has known 3-D structure to support druggability prediction, assay development, hit selection, lead optimisation.
  • Target is assayable, preferable in a biochemical and cellular format plus a phenotypic assay to allow orthogonal testing.

The two most important properties are functional relevance and druggability. By using biologicaly active compounds (druggability) which affect cancer relevant phenotypes (functional relevance) as a starting point for target identification, we will create a basis for more fruitful cancer drug discovery.

Assay Development and Screening

© dkfz.de

Assay Development and Screening is done at the Chemical Biology Core Facility.  The facility is a collaboration between EMBL, the German Cancer Research Center (DKFZ) and the University of Heidelberg (since February 2012) to provide the infrastructure and expertise to open up small molecule discovery to research groups at all three institutions.

Synthetic Organic Chemistry (Dr. Aubry Miller)

Our chemistry group is focused on the laboratory synthesis of new chemical entities for cancer research and therapy. Our work is conducted in two complementary ways.

Medicinal Chemistry: We design and synthesize small-molecule inhibitors of novel drug targets that have been identified and validated at the DKFZ. In close collaboration with the  Chemical Biology Core Facility, we transform HTS hits into potent and selective lead compounds for use as potential therapies and/or research tools.

Natural Product Synthesis: We also pursue the de novo synthesis of bioactive secondary metabolites. Natural products are carefully chosen on the basis of their chemical structure and biological activity. Judicious choice of a target natural product provides the opportunity to work at the frontiers of chemical synthesis and gives an unparalleled education to organic chemistry students.

Biological Testing (Dr. Mona Malz; Dr. Eberhard Amtmann)

Functional staining of cells. Loss of immortality in cancer cells. Senescent, cells produce the enzyme beta-galactosidase and are stained blue.

Novel, highly selective strategies for cancer treatment must be evaluated in suitable biological systems. With the aid of such tests the developmental potential of drug candidates can be estimated. For demonstrating the specific cellular effect of a drug, specific staining methods are used. Such staining methods have to be specific for the expected biological effect in a tumor cell, for example respiratory activity, energy supply, and immortalization. We use a collection of human normal cells and human cancer cell lines for assaying compounds for selective antitumoral activity. Activity in specific tumor types (e.g. lung cancer) or in specific tumor cell sub-populations can be identified by this method. An additional important feature of a drug candidate is its organismal therapeutic efficacy, in the absence of significant side effects. We compare antitumor activity in human cancer cells transplanted in immunodeficient mice with side effects, such as loss of body weight.

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