Nearly 20% of all human tumors have been linked to mutations in the RAS family of proteins making RAS one of the most sought after targets for chemotherapeutic intervention. Within the RAS family, oncogenic mutations in the isoform, KRAS, account for nearly 85% of all of those mutations. Despite significant research efforts, the development of small-molecule pharmacologic agents targeted at RAS has been largely unsuccessfully. As an alternative, we are seeking to identify D-peptide ligands of KRAS mutants targeted at KRAS protein-protein interactions as potential cancer therapeutics. Using the tools of chemical synthesis, we will generate homogeneous KRAS mutants using D-amino acids. These D-enantiomers of our target oncogenic mutants will be screened against large peptide libraries utilizing mirror-image phage display technology. Taking advantage of the principles of this technology, L-peptide ligands of D-KRAS mutants will be prioritized according to binding affinity. This accomplished, the corresponding peptides in the D-series will be synthesized. Of course these will have equal affinities with the endogenous L-KRAS mutants. Their biological activity will then be examined. This proposal describes an early-stage cancer drug development program that appears to have great promise for identifying lead compounds to be advanced into pre-clinical drug development in the future.
This research program is focused on the discovery of new peptide-based inhibitors of KRAS, a protein found to be mutated in approximately 20% of tumors, including those found in pancreatic, lung, and colorectal cancers. KRAS targets will be chemically synthesized and screened against large peptide libraries to identify lead compounds that can offer insight into the role these mutations play in cancer, as well as offer potential new therapeutic leads for the treatment of these cancers.
| Levinson, Adam M; McGee, John H; Roberts, Andrew G et al. (2017) Total Chemical Synthesis and Folding of All-l and All-d Variants of Oncogenic KRas(G12V). J Am Chem Soc 139:7632-7639 |
