Abstract

Chromatin-targeting Small Molecules as Cell Fate Modulators

Stefan Kubicek, Head, CeMM Research Center for Molecular Medicine

Chromatin modifying enzymes have emerged as key targets in cancer, and many of these factors act as oncogenes and tumor suppressor genes. Accordingly, small molecules targeting histone deacetylases and DNA methyltransferases are now approved drugs, and compounds for many more of the approximately 200 chromatin modifying enzymes are currently in preclinical development. In addition to cancers with genetic mutations in chromatin genes, these drugs may also be beneficial for exploiting synthetic lethalities and non-oncogene addictions. As the central structure that regulates access to DNA, chromatin integrates all signaling pathways to ensure tightly regulated gene expression. Therefore, chromatin pathways are hubs, which are highly enriched in genome-wide synthetic lethality screens. We describe our efforts to develop highly potent and selective chemical probes to target histone lysine methylation pathways and their application in proliferation control and cellular transdifferentiation.