Resumen de Biophysical and structural approaches to discover small-molecule modulators of challenging targets in cancer
Advances in structural and molecular biology have increased the knowledge of relevant and undrugged targets and have favoured the rational development of novel drugs through structure-based drug design (SBDD). Computational techniques are widely employed in SBDD, resulting as inexpensive, rapid and efficient tools for hit discovery and optimization. Hits from computational approaches have then to be assessed experimentally. Biophysical techniques are ideal candidates for hit validation, since they can directly study compound binding to a particular target. Biophysical techniques can provide deep knowledge of target-compound interactions ranging from binding assessment to binding site determination or information about the atomic structure of the target-compound complex. Overall, the combination of computational and biophysical techniques is a strategy that can enhance our ability to modulate challenging and undruggable targets in early-stage drug discovery.
E3 ligases have been described as relevant targets in cancer. Besides, the irruption of the targeted protein degradation technology has situated this target family in the forefront. In the present thesis we have applied a structure-based approach in order to study E3 ligases ligandability. This study has provided valuable information of the binding preferences of the studied proteins, while illustrating the possibility to increase the number of binders of these challenging family. Being FBW7 E3 ligase one of the most mutated proteins in cancer, we have used the previous information to identify and characterize small molecules that bind to this E3 ligase by combining computational and biophysical techniques. These small molecules could be a point of departure to develop drugs able to modulate this E3 ligase.
TET2 is a tumour suppressor that losses its function by mutations or gene repression in different types of cancer, particularly hematologic. Besides, inhibition of TET2 has been described to have a therapeutic interest due to its implication to cancer relapse.
Potential TET2 modulators have been developed following a structure-based approach.
In the present thesis we have developed and characterized TET2 modulators applying biophysical techniques.
Bromodomains have been recently described for their interest in cancer. Specifically, BRD4 has also been used as a test system for computational techniques due to its ease of production and constant behaviour. Computer-aided drug design faces several challenges, being the prediction of solvation preferences and fragment evolution two of them. On one hand, we have applied computational tools to study the solvation preferences of BRD4 BD1. With that information, we have developed and characterized novel chemical entities. On the other hand, fragments interacting with BRD4 BD1 have been identified by an automated fragment evolution platform developed in our group.
In the present thesis, interactions of the evolved fragments with BRD4 BD1 have been characterized. The resulting information has helped to validate the applied computational tools and could be used to develop novel BRD4-based therapies.
