Grant: Project Grant

Activating mutations in Ras genes are among the leading drivers in human cancer. The prevalence of Ras genetic lesions is especially high in pancreatic (>90%), colorectal (50%), and lung (30%) cancers. We propose herein a two-pronged strategy to develop small molecule modulators that will block Ras activity in human cancer cells and therefore provide drug candidates for several deadly cancers. We recently identified a series of chemical inhibitors by high-throughput screening with an assay detecting the interaction of Ras with its effector RAF. These molecules were found to inhibit oncogenic signaling and proliferation in Ras-mutant cancer cell lines. We now need mechanistic characterization of these compounds in order to further optimize them and improve their effectiveness. More specifically, we will confirm the binding of these compounds to Ras-ERK pathway components and we will assess their selectivity by biophysical, biochemical and genetic approaches. In a second approach, we will develop compounds mimicking a synthetic protein, named NS1 that binds to Ras with high-affinity. NS1 was recently developed by our collaborators and was shown to block oncogenic signaling and the proliferation of cancer cells (Spencer-Smith et al. Nat. Chem. Biol.). We will exploit this privileged information to rationally design and synthesize Ras inhibitors. The NS1 crystal structure with Ras will be used as a template for computer-assisted molecular modeling. Mimicking protein-protein interactions with small molecules has historically been challenging. We therefore propose to synthesize larger molecules, named macrocyclic peptides, designed to interact over an extended surface while retaining drug-like properties. The two aims of this proposal represent innovative strategies to inhibit Ras function in human tumors. It can be expected that compounds emerging from these approaches will form the ground of effective treatments for many common cancers bearing activating Ras mutations.