FEB 27, 2019 07:30 AM PST

Keynote Presentation: Second Harmonic Generation Detection of Ras Conformational Changes and Discovery of a Novel Small-Molecule Binder

Speakers
  • Professor of the UCSF Helen Diller Family Comprehensive Cancer Center
    Biography
      Frank McCormick, PhD, FRS, is Professor of the UCSF Helen Diller Family Comprehensive Cancer Center. Prior to joining the UCSF faculty, Dr. McCormick pursued cancer-related work with several Bay Area biotechnology firms and held positions with Cetus Corporation (Director of Molecular Biology, 1981-1990; Vice President of Research, 1990-1991) and Chiron Corporation, where he was Vice President of Research from 1991 to 1992. In 1992 he founded Onyx Pharmaceuticals, a company dedicated to developing new cancer therapies, and served as its Chief Scientific Officer until 1996. At Onyx Pharmaceuticals, he initiated and led drug discovery efforts that led to the approval of Sorafenib in 2005 for treatment of renal cell cancer, and for liver cancer in 2007, and the approval of ONYX-015 in 2006 in China for treatment of nasopharyngeal cancer. Sorafenib is being tested in multiple indications worldwide. In addition, Dr. McCormick's group led to the identification of a CDK4 kinase inhibitor. Dr. McCormick's current research interests center on the fundamental differences between normal and cancer cells that can allow the discovery of novel therapeutic strategies.

      Dr. McCormick holds the David A. Wood Chair of Tumor Biology and Cancer Research at UCSF. Dr. McCormick is the author of over 285 scientific publications and holds 20 issued patents. He also served as President, 2012-2013 for the American Association for Cancer Research (AACR). More recently, he has taken a leadership role at the Frederick National Lab for Cancer Research, overseeing an NCI supported national effort to develop therapies against Ras-driven cancers. These cancers include most pancreatic cancers, and many colorectal and lung cancers, and are amongst the most difficult cancers to treat.

    Abstract:

    Second harmonic generation (SHG) is a biophysical method that sensitively measures real-time conformational change of biomolecules attached to membranes. SHG has recently been applied to detect protein conformational changes in the presence of biological ligands and small molecules. I will describe implementation of SHG as a primary screening platform to identify novel fragment ligands to oncogenic KRas. KRas is the most frequently mutated driver of pancreatic, colon, and lung cancers; however, there are few well-characterized small molecule ligands due to a lack of deep binding pockets. Using SHG, we identified a novel fragment binder to KRasG12D and then used 1H 15N HSQC NMR to characterize its binding site as a pocket adjacent to the Switch II region. The unique sensitivity of SHG furthered our study by revealing distinct conformations induced by our hit fragment compared to DCAI, a Ras ligand previously described to bind the same pocket, identified by fragment based NMR screening. This study highlights SHG as a high-throughput screening platform that reveals structural insights in addition to ligand binding.

    Learning Objectives: 

    1. Ras proteins, once considered “undruggable”, are now being subjected to a variety of new chemical and biophysical techniques to identify potential drugs that bins to shallow pockets in the protein
    2. The biophysical phenomenon referred to as second harmonic generation (SHG) can be used as a tool for discovering molecules that bind to proteins of interest


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