Identification of novel epigenetic modulators of CBP-like bromodomains for the analysis of their therapeutic potential

• Applicants: Professor Dr. Stefan Günther; Dr. Daniel Wohlwend
• Subject Area: Pharmacy ; Biochemistry ; Bioinformatics and Theoretical Biology ; Structural Biology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 259316432

Epigenetic mechanisms are heritable changes in gene activity that occur without alteration in DNA sequence. These non-genetic alterations are tightly regulated by histone proteins associated with DNA. Specific writer and eraser proteins modify residues of the histone tails which are in turn recognised by histone tail reader proteins. Functionally, the patterns of epigenetic modifications are translated into modulated expression levels and thus serve as epigenetic markers for gene expression and chromatin organisation during the cell cycle. Several human diseases, including cancer, show altered signalling pathways affected by changes in the activity levels of epigenetic modulators. Consequently, the medical relevance of these proteins has made the pharmacological manipulation of these processes an area of intense research. Recently, small-molecule inhibitors for the bromodomain and extra-terminal (BET) bromodomain family of acetylation readers have shown early promise in the treatment of the genetically defined midline carcinoma and hematopoietic malignancies. In addition to the BET family, there are dozens of other bromodomains whose therapeutic potential has often not been discovered yet. The CBP-like family for instance contains six members of closely related bromodomains. For some of them the role in malignancies remains elusive, while for others, as for the eponymous CREB-binding protein (CBP) itself, there are clear indications for their high potential as novel therapeutic targets. However, only little success was made in identifying potent inhibitors against the CBP-like family. The identification of small molecules inhibiting the bromodomains of this family is therefore of prime importance and the very aim of this research project. The project will start with the initial selection of candidate molecules by large-scale fragment-based in silico screenings to all six members of the CBP-like family. A highly-potent fragment, which we could identify in our previous work, will serve as starting point for these screenings. The project will continue with the experimental validation of the predictions using isothermal titration calorimetry, and crystallisation and X-ray structure analysis of the identified novel compounds in complex with their targets. The obtained data will be the basis for the optimisation of the hits toward high-affinity binders via model based lead optimisation. The therapeutical potential will be further analysed by in vitro tests on relevant cell lines. The analysis will be complemented by gene expression profiling to assess the impact of newly identified inhibitors on the cell. Finally, the project will contribute to providing new drugs against currently only hardly or even non-treatable malignancies.

• DFG Programme: Research Grants