The Ras protein is found in many cancers, including myeloid leukemias. Despite its important role in cancer, there are no known drugs to block it. There are multiple Ras proteins, including KRas and NRas that are found in a variety of leukemias. The unique properties of Ras preclude a clear path to drug discovery using the approaches that have worked with the drug targeting of many other proteins. Thus, we are using a new approach based on a knowledge of Ras function to target its oncogenic activity. Ras proteins cycle between on and off states, and this cycling is regulated by a protein called SOS1. The association of Ras and SOS1 is critical for placing Ras back in an activated state that the cancer uses to promote its own pathogenic survival. Our laboratory has a long standing interest in a novel approach using stapled peptides to block the function of oncogenic proteins. By mimicking only a small portion of the SOS1 protein that interacts with Ras, and using a peptide-stapling technology that reinforces the structure of such peptides, we discovered a prototype compound that directly disrupts the SOS1/KRas complex, inhibits a broad spectrum of cancer-causing KRas proteins, and kills cancer cells as a result. Surprisingly, we also found that our compound can independently block KRas activity by another unknown mechanism. I will apply analytical approaches from a variety of fields, including chemistry, structural biology, leukemia biology, and translational medicine to investigate how our prototype stapled peptides directly block the activity of KRas and to determine whether it also blocks NRas activity. I will chemically synthesize a large tool box of SOS1-based stapled peptides and characterize their functional interactions with Ras family proteins and their cancer-causing mutant forms. I will then use structural biology methods to interrogate this new mechanism of direct Ras blockade by stapled peptides, and generate blueprints of their inhibitory interactions with Ras proteins, which is a critical step for developing optimal drugs. Using a series of assays that measure cancer cell death, I will test the best inhibitors that emerge and determine the relative susceptibilities of various Ras-driven leukemia cell lines to the drugs. Importantly, I will evaluate the anti-tumor activity of our best stapled peptides in mouse models of leukemia driven by Ras proteins. I anticipate that my research will reveal a novel mechanism for targeting Ras and provide a new therapeutic strategy to induce cancer cell death in patients suffering from myeloid leukemias driven by Ras.