Combined rational design and a high throughput screening platform for identifying chemical inhibitors of a Ras-activating enzyme.

ABSTRACT: The Ras family small GTPases regulate multiple cellular processes, including cell growth, survival, movement, and gene expression, and are intimately involved in cancer pathogenesis. Activation of these small GTPases is catalyzed by a special class of enzymes, termed guanine nucleotide exchange factors (GEFs). Herein, we developed a small molecule screening platform for identifying lead hits targeting a Ras GEF enzyme, SOS1. We employed an ensemble structure-based virtual screening approach in combination with a multiple tier high throughput experimental screen utilizing two complementary fluorescent guanine nucleotide exchange assays to identify small molecule inhibitors of GEF catalytic activity toward Ras. From a library of 350,000 compounds, we selected a set of 418 candidate compounds

SUBMITTER: Evelyn CR 

PROVIDER: S-EPMC4432303 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature