Head, Christian Doppler Laboratory for Chemical Epigenetics and Anti-Infectives

Head, Chemical Screening and Platform Austria for Chemical Biology (PLACEBO)
Head, Proteomics and Metabolomics Facility

Stefan Kubicek
Chemical Epigenetics

 

 

Chromatin modifying enzymes alter epigenetic marks to regulate a plethora of biological processes. Our group is interested in understanding how these enzymes control cell fate in health and disease. Using cell and chemical biological approaches we are studying the role of histone methylation in cancer and diabetes, and are searching for new ways of targeting chromatin modifying enzymes with small molecules.

I also head the Platform Austria for Chemical Biology (PLACEBO), which provides chemical biology technologies including high-throughput screening and chemical proteomics to the scientific community.

Chemical biology of histone lysine methylation pathways in cancer

Chromatin aberrations play causative roles in leukemia and solid tumors, where epigenetic modifiers are often aberrantly expressed or genetically altered. Our goal is to systematically study the role of the approximately 400 chromatin modifying proteins in cancer development and progression, and identify key players as potentially druggable targets.

Based on results from our epigenome-wide shRNA screens, we have focused on small molecules that inhibit the writers, readers and erasers of histone lysine methylation. Such compounds will be used as chemical probes to study the function of these proteins, and could also be further developed into new anti-cancer drugs.

Chromatin in the specification of pancreatic cell types

Epigenetic modifications play important roles in cell type specification, and small molecule inhibitors of several chromatin modifying enzymes have been shown to increase the efficiency of cellular reprogramming. We hypothesize that targeting chromatin can contribute to the formation of therapeutically relevant cell types for regenerative medicine by promoting cellular transdifferentiation.

We use functional genomics and chemical biology probes, which modulate the activities of chromatin modifying enzymes, to understand epigenetic plasticity in the pancreas. Our goal is to convert other cell types to insulin-producing pancreatic beta-like cells, which could be used to develop an alternative approach for treating diabetes.

Christian Doppler Laboratory for Chemical Epigenetics and Anti-Infectives

This is a public-private partnership between CeMM, Boehringer Ingelheim, and Haplogen. It aims to develop novel screening technologies and identify chemical probe compounds as a basis for future drug development projects with the corporate partners.

In the chemical epigenetics module we develop technologies in collaboration with Oncology Research at Boehringer Ingelheim RCV GmbH & Co KG to identify and characterize small molecules and druggable proteins regulating chromatin structure and function. In a second module, we identify chemical probes for host factors of infectious diseases based on molecular targets derived by a powerful screening approach using human haploid cells implemented at Haplogen GmbH. Bringing these targets together with CeMM’s comprehensive compound library and screening expertise will generate novel chemical probes that can be used for proof-of-concept studies.

Biosketch

Stefan Kubicek studied organic chemistry in Vienna and Zürich. He received his Ph.D. in Thomas Jenuwein’s group at the IMP in Vienna followed by postdoctoral work with Stuart Schreiber at the Broad Institute of Harvard and MIT in the U.S. He joined CeMM in 2010.

Selected Papers

Kubicek, S et al. Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells. Proc Natl Acad Sci U S A 2012; 109:5364-9. (abstract)

Luo, X et al. A selective inhibitor and probe of the cellular functions of Jumonji C domain-containing histone demethylases. J Am Chem Soc 2011; 133:9451-6. (abstract)

Fomina-Yadlin, D et al. Small-molecule inducers of insulin expression in pancreatic alpha-cells. Proc Natl Acad Sci U S A 2010; 107:15099-104. (abstract)

Kubicek, S et al. Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell 2007; 25:473-81. (abstract)