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RAS Chat: An Interview with Kevan Shokat and Ziyang Zhang
Kevan Shokat is a professor at the University of California at San Francisco and leader in the search for novel targeted therapeutics. He successfully developed the first covalent inhibitor of mutant KRAS (Sotorasib), which saw FDA approval in 2021 for the treatment of adults with non-small cell lung cancer (NSCLC) that carry the KRAS G12C mutation. Ziyang Zhang is a bright young mind in the field of chemical biology. He completed his post-doc with Dr. Shokat and started his own lab at the University of California Berkeley in 2022, where he focuses on the development of new mutant-specific covalent ligands and chemical modulators of the adaptive immune response. Megan Rigby works in the RAS Initiative’s Drug Screening and Preclinical Research group where she contributes to the search for novel KRAS mutant-specific covalent and non-covalent inhibitors, and aids in efforts to further understand fundamental RAS biology. Thomas Turbyville heads the RAS POSTED: 6/26/2023
Consensus on the RAS Dimerization Hypothesis
Dhirendra Simanshu leads the structural biology efforts at the NCI RAS Initiative, Frederick National Laboratory for Cancer Research. His research focuses on the structural characterization of KRAS in complex with various regulators and targeting druggable pockets using structure-based drug design. John Hancock is executive dean of McGovern Medical School at the University of Texas Health Science Center at Houston. His research is focused on the plasma membrane interactions of RAS proteins and how the spatiotemporal organization of membrane lipids contributes to the assembly and regulation of RAS signaling complexes. Mark Philips is a Professor of Medicine, Cell Biology and Biochemistry in the Perlmutter Cancer Center at NYU Grossman School of Medicine. He has directed a molecular cell biology laboratory for 30 years focused on the post-translational modification and membrane targeting of RAS and related small GTPases. His many contributions to the field include characterization of isoprenylcysteine carboxylmethyltransferase, endomembrane trafficking and POSTED: 5/2/2023
KRASG12C inhibition drives anti-tumour immunity in lung cancer but combinations with anti-PD1 immunotherapy may only benefit patients with ‘inflamed’ tumours
Jesse Boumelha works in Julian Downward’s lab at the Francis Crick Institute, where he was recently awarded his PhD. His research focuses on understanding mechanisms of immune evasion in novel mouse models of KRAS-mutant lung cancer in order to develop rational immunotherapy combinations. Edurne Mugarza is a former graduate student in the Downward lab at the Francis Crick Institute working on KRAS-G12C inhibitors and their influence on the tumour microenvironment and anti-tumour immunity. She is currently a postdoctoral researcher at UCLA with Cristina Puig Saus. Sophie de Carné Trécesson is a postdoc in the Downward lab at the Francis Crick Institute where her work focuses on how KRAS signaling shapes the tumour microenvironment using single cell technologies. Febe van Maldegem was a postdoc in the Downward at the Francis Crick Institute until last year and now leads her own lab in the Department of Molecular Cell Biology & Immunology at POSTED: 11/14/2022
The use of Molecular Docking as a ligand discovery tool; Can machine learning help the pursuit for ligands?
Trent E. Balius is one of the developers of the UCSF DOCK Exit Disclaimer software, which is a computational tool used to predict how a small molecule (ligand) binds a site on a protein (or other macromolecule). Trent leads the RAS Computational Chemistry team at the NCI RAS Initiative, where he uses molecular docking to search for novel RAS-targeted therapeutics. He received his PhD from Stony Brook University Exit Disclaimer studying Computational Biology in the Department of Applied Mathematics and Statistics Exit Disclaimer under the direction of Robert C Rizzo Exit Disclaimer, and performed his postdoctoral training in the Shoichet Laboratory Exit Disclaimer, in the Department of Pharmaceutical Chemistry Exit Disclaimer at the University of California, San Francisco (UCSF) Exit Disclaimer. Megan Rigby is a member of the Covalent Inhibitors group at the RAS Initiative as a Research Associate II. She is currently completing her graduate studies in Biomedical Science POSTED: 7/6/2022
Could CryoEM structures of neurofibromin lead the way to better therapeutic approaches for Neurofibromatosis type 1?
Dom Esposito has directed the Protein Expression Laboratory of the NCI’s Frederick National Lab since 2011, and currently leads the RAS Reagents Core, which provides DNA cloning, protein expression and purification, and qualified cell lines to the NCI RAS Initiative . He earned his Ph.D. in Biochemistry and Biophysics at Johns Hopkins University and did postdoctoral work in the Laboratory of Molecular Biology at the National Institute of Diabetes and Digestive and Kidney Diseases. Recently, three groups ( https://pubmed.ncbi.nlm.nih.gov/35353986/, https://pubmed.ncbi.nlm.nih.gov/34887559/, https://pubmed.ncbi.nlm.nih.gov/34707296/) reported detailed molecular structures of the neurofibromin protein responsible for the genetic disorder Neurofibromatosis type 1 (NF1). This disease impacts 1 in 2,000 adults and leads to neurological issues as well as an increased risk for benign and malignant nerve and skin tumors. The neurofibromin protein is a GTPase activating protein (GAP) responsible for turning off RAS activity, and defects in this large 2818 amino acid protein lead to POSTED: 5/18/2022
Sin1: a novel RAS effector with isoform specificity
Pau Castel is an Assistant Professor at the Department of Biochemistry and Molecular Biology at New York University School of Medicine. His research is focused on the study of oncoproteins in cancer and genetic disorders. The Castel lab uses biochemical, signal transduction, and mouse genetics to elucidate the function of oncogenic pathways, including RAS and PI3K signaling. Dhirendra Simanshu leads the structural biology efforts at the NCI RAS Initiative, Frederick National Laboratory for Cancer Research. His research focuses on structural characterization of KRAS in complex with various regulators and targeting druggable pockets using structure-based drug design. RAS proteins work as molecular binary switches that regulate cellular growth by cycling between inactive GDP- and active GTP-bound states. In humans, three RAS genes encode four different RAS isoforms—HRAS, NRAS, KRAS4A, and KRAS4B—with the last two KRAS isoforms arising from alternative splicing of the fourth KRAS exon. All four RAS isoforms share high POSTED: 2/22/2022
Simulating Ras: 30 years of progress
Chris Neale is a Staff Scientist at the Los Alamos National Laboratory in New Mexico. His research focuses on computational drug discovery and membrane protein biophysics. The first crystal structures of Ras arrived more than thirty years ago. 1,2 Within only a few years, its structure and dynamics were being simulated on computers. 3,4 As with many things in science, progress was rapid. Whereas these early simulations probed solution systems on sub-nanosecond time scales, recent ensembles of simulations of Ras protein(s) on mixed lipid bilayers attained aggregate time scales exceeding a millisecond using all-atom models, 5 and exceeding 200 milliseconds using coarse-grained models in which each protein residue is represented by 2-5 beads. 6 Together, computer simulations and associated theoretical modeling approaches have made important contributions to our current understanding of Ras’s disposition with respect to the membrane surface and the nature of Ras’s interactions with its effector kinase Raf POSTED: 2/1/2022
RAS Initiative Leadership Change
On December 31, 2021, NCI RAS Initiative Program Officer, Dr. Sara Hook, left federal service to join the Medical University South Carolina Hollings Cancer Center. We extend a heartfelt thank you to Dr. Hook for her continued dedication, guidance, and support to the program since its inception in 2013. She worked tirelessly with NCI and Leidos Biomedical Research leadership to give life to the RAS Initiative concept and spent the past eight years collaborating with NCI RAS Initiative researchers resulting in the program’s continued success. We also extend a warm welcome to Dr. Christopher Kane who is assuming the Program Officer role. Dr. Kane is a research and development leader with eleven years of private sector biopharmaceutical experience spanning drug discovery to phase II clinical trials. He subsequently led preclinical research and early advanced development activities for eight years at USAMRIID, with a primary focus on small molecule therapeutics targeting POSTED: 1/20/2022
KRAS-related long noncoding RNAs in human cancers
Reza Ahmadian, a professor of Biochemistry & Molecular biology at the Heinrich-Heine University Düsseldorf, works on the molecular mechanisms of disease-related signaling pathways by (i) purifying and identifying native RAS/RHO protein complexes in cell-specific context and subcellular sites, (ii) elucidating the structure-function relationships of protein-protein and protein-ligand interactions, (iii) characterizing and in vitro reconstituting signaling networks in solution and on synthetic liposomes, and (iv) identifying and validating new interacting surfaces as potential drug target sites. Mahsa Saliani, a PhD student in Biochemistry at the Ferdowsi university of Mashhad in Iran, works together with Ahmadian Group on understanding KRAS-driven cancers by studying KRAS-related oncogenic lncRNAs and their potential role in KRAS signal transduction. Intensive efforts to understand the mechanisms underlying the intracellular trafficking, regulation, and signaling pathways of KRAS have suggested several therapeutic strategies 1. Despite its well-recognized importance in cancer promotion, only a few efforts in the past four decades POSTED: 12/7/2021