title: Rational design of small molecule inhibitors targeting the Ras GEF, SOS1.
abstract: Ras GTPases regulate intracellular signaling involved in cell proliferation. Elevated Ras signaling activity has been associated with human cancers. Ras activation is catalyzed by guanine nucleotide exchange factors (GEFs), of which SOS1 is a major member that transduces receptor tyrosine kinase signaling to Ras. We have developed a rational approach coupling virtual screening with experimental screening in identifying small-molecule inhibitors targeting the catalytic site of SOS1 and SOS1-regulated Ras activity. A lead inhibitor, NSC-658497, was found to bind to SOS1, competitively suppress SOS1-Ras interaction, and dose-dependently inhibit SOS1 GEF activity. Mutagenesis and structure-activity relationship studies map the NSC-658497 site of action to the SOS1 catalytic site, and define the chemical moieties in the inhibitor essential for the activity. NSC-658497 showed dose-dependent efficacy in inhibiting Ras, downstream signaling activities, and associated cell proliferation. These studies establish a proof of principle for rational design of small-molecule inhibitors targeting Ras GEF enzymatic activity.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: Chris R
authors.initials: CR
authors.lastname: Evelyn
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Duan
authors.affiliation: Division of Biomedical Informatics, Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: Jacek
authors.initials: J
authors.lastname: Biesiada
authors.affiliation: Division of Oncology, Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Seibel
authors.affiliation: Division of Biomedical Informatics, Children's Hospital Research Foundation, Cincinnati, OH 45229, USA; Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Meller
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, OH 45229, USA. Electronic address: yi.zheng@cchmc.org.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D016296:Mutagenesis; D020837:SOS1 Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D020837:SOS1 Protein; D054852:Small Molecule Libraries