DrugRas: design, synthesis, testing and characterization of compounds against oncogenic K-Ras mutants
Development of K-Ras-G12C inhibitors is planned to be accomplished from several different directions. Known K-Ras-G12C inhibitors are going to be modified by the best functional groups of our so-called warhead-mapping library. These compounds are going to be selected based on NMR measurements, their covalent binding being confirmed by NMR spectroscopy and MS/MS measurements. In addition, with the structural extension of electrophilic fragment hits from a prevalent screening campaign, we aim to develop additional covalent K-Ras-G12C inhibitors by comparing and merging the structures of the known inhibitors with our fragments. Moreover, taking into account the analogous structural elements of different K-Ras mutants, we attempt to identify new possibilities to inhibit other oncogenic mutant K-Ras proteins as well. Mapping of the active site of K-Ras could help to identify the structure of more inhibitor sin the future, therefore nucleotide-analogue electrophilic compounds are going to be designed and synthesized in order to bind to the corresponding residues of the active center. This binding is going to be confirmed also by NMR spectroscopy and MS/MS measurements. Using a different approach, a small molecule or an oligopeptide is also going to be designed based on the Ras binding domain of GTPase activating (GAP) protein. This molecule would enhance the reduced hydrolysis rate of mutant Ras proteins. We aim to synthesize and test 10-15 molecules altogether using the previously mentioned several approaches. The inhibitory effect of the prepared compounds is going to be assessed by cell-based assays.
Gyula Pálfy, Péter Ábrányi-Balogh, Zoltán Orgován, István Vida, László Petri, András Perczel, György M. Keserű