Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.27.218248v1?rss=1 Authors: Carta, L., Hutcheson, R., Davis, S. A., Rudolph, M. J., Reynolds, C. H., Quick, M., Williams, T. M., Schmertzler, M., Hadari, Y. R. Abstract: RAS genes encode small GTPases essential for proliferation, differentiation, and survival of mammalian cells. RAS gene mutations are associated with approximately 30% of all human cancers. However, based on measurements reported three decades ago of Ras protein affinities to GTP in the 10-20 picomolar range, it has been accepted in the scientific and medical communities that Ras proteins are undruggable targets. Here, we report MicroScale Thermophoresis and scintillation proximity assay measurements of the affinity of K-Ras and several K-Ras mutants for GTP in the range of 200 nanomolar, a 10,000-fold difference from that previously reported, and the identification of over 400 small molecules that block GTP binding to K-Ras. Focusing on two of those molecules, we report small molecule inhibition of Ras downstream signaling and cellular proliferation in human pancreatic and non-small cell lung cancer cells expressing wild type and K-Ras G12C, G12D and G12S, and N-Ras Q61K mutants. Copy rights belong to original authors. Visit the link for more info