Erforschung und Erschließung sekundärer Bindungsstellen der Proteinkinase CK2 (XPLOR_CK2)

Basic data for this project

Description

CK2 is upregulated in many types of cancer and thus an attractive pharmaceutical target. The typical target region for inhibition of CK2 and other protein kinases is the ATP cavity, therefore often referred to as "primary'' site. Due to the conservation of the ATP site, ATP-competitive inhibitors are limited in their selectivity. A strategy to overcome this issue is the use of a "secondary'' binding site that can be addressed either alone or in combination with the ATP site by a so-called bivalent inhibitor. Typical secondary sites are the substrate binding region and allosteric sites located remote of the active centre: Allosteric sites can be preformed or "cryptic", i.e. not open in the apo-form and becoming accessible only in the presence of a suitable ligand. An attractive secondary site cf CK2α and CK2α' is the αD pocket, a cryptic site accessible only after conformational adaptations cf the helix αD region. In the XPLOR_CK2 project, the αD packet will be exploited to construct highly potent, selective and cell permeable bivalent CK2 inhibitors with indenoindole-based ATP-competitive anchor groups. lf possible, the selectivity shall be boosted even to a level that allows the distinction of the two isoforms CK2α and CK2α'. Selected bivalent inhibitors from these activities will be used to determine high-resolution crystal-structures of  the CK2 holoenzymes based on either CK2α or CK2α'.