Delving into the Latest Updates on NSC-658497 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

RAS x SOS1

Mechanism

RAS inhibitors(RAS type GTPase family inhibitors), SOS1 inhibitors(Son of sevenless homolog 1 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

Children's Hospital Research Foundation

Active Organization

Children's Hospital Research Foundation

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC20H10N2O6S2

InChIKeyDJFUFNNDOAUACG-UHFFFAOYSA-N

CAS Registry909197-38-2

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.

100 Deals associated with NSC-658497

Login to view more data