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Ref Type Journal Article
PMID (25825487)
Authors Evelyn CR, Biesiada J, Duan X, Tang H, Shang X, Papoian R, Seibel WL, Nelson S, Meller J, Zheng Y
Title Combined rational design and a high throughput screening platform for identifying chemical inhibitors of a Ras-activating enzyme.
Journal The Journal of biological chemistry
Vol 290
Issue 20
Date 2015 May 15
URL
Abstract Text 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 predicted to disrupt the GEF-Ras interaction, of which dual wavelength GDP dissociation and GTP-loading experimental screening identified two chemically distinct small molecule inhibitors. Subsequent biochemical validations indicate that they are capable of dose-dependently inhibiting GEF catalytic activity, binding to SOS1 with micromolar affinity, and disrupting GEF-Ras interaction. Mutagenesis studies in conjunction with structure-activity relationship studies mapped both compounds to different sites in the catalytic pocket, and both inhibited Ras signaling in cells. The unique screening platform established here for targeting Ras GEF enzymes could be broadly useful for identifying lead inhibitors for a variety of small GTPase-activating GEF reactions.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
UC-773587 UC-773587 1 0
UC-857993 UC-857993 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
UC-773587 UC-773587 is a small molecule inhibitor of SOS1, which blocks SOS1- RAS interaction and SOS-1 mediated RAS activation, potentially leading to decreased growth of SOS1 dependent tumor cells (PMID: 25825487).
UC-857993 UC-857993 is a small molecule inhibitor of SOS1, which blocks SOS1- RAS interaction and SOS-1 mediated RAS activation, potentially leading to decreased growth of SOS-1 dependent tumor cells (PMID: 25825487).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown prostate cancer not applicable UC-857993 Preclinical Actionable In a preclinical study, UC-773587 inhibited ERK activation and growth of prostate cells in culture (PMID: 25825487). 25825487
Unknown unknown prostate cancer not applicable UC-773587 Preclinical Actionable In a preclinical study, UC-773587 inhibited ERK activation and growth of prostate cells in culture (PMID: 25825487). 25825487