DrugRas: design, synthesis, testing and characterization of compounds against oncogenic K-Ras mutants 2.

Based on our previous results, we continue the development of K-Ras inhibitors in different directions. The structure of the already known K-Ras-G12C inhibitors and the best hits of our electrophilic fragment library are going to be compared, then merged leading to the development of new inhibitors. We compare the effect of different electrophilic warheads and side chains in order to find optimal compounds. Binding of the synthesized compounds to the target protein will be proved by NMR measurements, while their inhibitory effect is going to be assessed by cell-based assays. Apart from the K-Ras-G12C mutant, we are also aiming to target K-Ras-G12D variant by screening of a non-covalent library. The binding regions are going to be determined by NMR spectroscopy, and their structure will be compared with other known inhibitors. We will develop further the new binders to K-Ras-G12D by computational modelling, and their activity is going to be assessed by cell-based assays. In addition, we design and synthesize new electrophilic nucleotide-analogues capable of binding to the appropriate side chain of the residues in the active centre, which can be proved by NMR and MS/MS methods. These results could contribute to the mapping of the nucleotide binding site of K-Ras, and the resulting information can be utilized in further inhibitor design.

György M. Keserű, Péter Ábrányi-Balogh, Zoltán Orgován, László Petri, András Perczel, Gyula Pálfy, István Vida