Mutations in Ras genes are the most common activators of cancer in humans, and effective inhibitors of the GTPases they encode have been sought as potential cancer therapeutics. Despite extensive research in this field, Ras proteins remain among the most challenging targets in medical chemistry. Oncogenic mutations in Ras genes typically result in proteins locked in the ?on? GTP-bound state, which binds its effectors Raf kinases and PI3K. Therefore, small molecules that target GTP-bound Ras proteins and disrupt interactions with effectors are expected to be promising cancer therapeutics. This proposal seeks to develop small molecule inhibitors of Ras(GTP) by targeting the recently discovered ?switch II groove.? The strategy combines techniques from synthetic chemistry, combinatorial chemistry, and chemical biology to increase the non-covalent affinity of binders, evaluate them as inhibitors of Ras(GTP), and develop N- and H-Ras oncogene-selective inhibitors. This research strategy was designed to both leverage my existing knowledge of synthetic chemistry and train me in new chemical biology techniques. The experimental work will require me to learn protein expression and purification, protein NMR spectroscopy, and a range of biochemical assays to detect inhibition of Ras GTPases. By reading the relevant literature and discussing this project with experienced scientists, I will greatly improve my understanding of the protein signaling pathways involved in cell growth and proliferation which are mis- regulated in cancer. UCSF is an ideal location for me to receive training in chemical biology due to its wide range of experienced faculty, excellent instrumentation facilities, and connections with the wider chemical biology community. I intend to pursue an academic career applying organic chemistry to the improvement of human health; specifically, I wish to develop new synthetic methodology to enable the discovery of inhibitors for challenging and dynamic protein targets. My academic studies and graduate research have given me a strong background in organic chemistry and synthetic methods; however, my formal training in chemical biology is lacking. I chose to join Professor Shokat?s group at UCSF because I believe he is an ideal mentor to help me remedy that lack and better prepare me for an independent career.
Mutations in Ras genes are the most common activating lesions of cancer in humans, and high-affinity inhibitors for Ras family GTPases are, therefore, expected to be promising cancer therapeutics. However, the development of such inhibitors has proven challenging, resulting in the characterization of Ras as an ?undruggable? target. This proposal describes a research program to develop inhibitors targeting a recently discovered binding site, the switch II groove.
