Room 304, Chemistry Building
Professor Kevan Shokat
University of California, San Francisco
Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response tostandard therapies. Efforts to directly target this oncogene have faced difficulties due to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatory sites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent upon relative nucleotide affinity and concentration. This gives GTP an advantage over GDP and increases the proportion of active GTP-bound Ras. I will discuss the development of small molecules that irreversibly bind to a common oncogenic mutant, K-RasG12C. These compounds rely on the mutant cysteine for binding and therefore do not affect the wild type protein (WT). Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. These data provide structure based validation of a novel allosteric regulatory site on Ras that is targetable in a mutant-specific manner. I will also discuss a new approach for blocking membrane localization of K-Ras.
Professor Shokat is a pioneer in the development of chemical methods for investigating cellular signal transduction pathways—with a particular focus on protein kinases and lipid kinases. Dr. Shokat uses a combination of chemical synthesis and protein engineering to create uniquely traceable and regulatable kinases, allowing the function of over 100 different kinases to be uncovered across all disease areas including oncology, metabolism, and infectious disease.
Kevan is currently an Investigator of the Howard Hughes Medical Institute, Professor in the Department of Cellular and Molecular Pharmacology, where he also served as Department Chair from 2010-2014 at the University of California at San Francisco. He is also Professor in the Department of Chemistry at the University of California at Berkeley. After receiving his Ph.D. in Organic Chemistry at UC Berkeley with Professor Peter Schultz, and post-doctoral work in immunology at Stanford University with Professor Chris Goodnow, Kevan began his independent research career at Princeton University where he was promoted from Assistant to Associate Professor in four years. He has received numerous awards including being named a Fellow of several prestigious research foundations including the Pew Foundation, Searle Foundation, Sloan Foundation, Glaxo-Wellcome Foundation, and the Cotrell Foundation. He has also received the Eli Lilly Award, given to the most promising biological chemist in the country under the age of 37. He was inducted into the National Academy of Sciences (2010), the Institute of Medicine (2011), and the American Academy of Arts and Sciences (2011).
Kevan has successfully commercialized discoveries from his laboratory. His development of chemical genetic tools for tracking and validating protein kinase drug targets is licensed by Artemis-Taconic for target validation of kinases in multiple disease areas. In 2007 he co-founded Intellikine, Inc. to commercialize a series of PI3K and mTOR small molecule inhibitors for cancer and inflammatory disease. In four years Intellikine has progressed three compounds into Phase I including INK1197 (PI3Kd)-now partnered with Infinity Pharmaceuticals, INK128 (mTOR), and INK1117 (PI3Ka). In December 2011, Intellikine was acquired by Takeda Pharmaceuticals. In 2013 he co-founded Araxes Pharmaceuticals in La Jolla, CA. Also in 2013 he co-founded eFFECTOR Pharmaceuticals in San Diego, CA.