AI Article Synopsis
- SOS1 is a key protein that helps activate RAS, which plays a vital role in various cellular functions, and its improper activation is linked to about 30% of human cancers, making SOS1 a potential target for cancer treatment.
- Researchers developed a new group of benzimidazole-derived compounds that act as SOS1 agonists, enhancing the exchange of GDP for GTP on RAS even at very low concentrations.
- These compounds not only bind effectively to SOS1 but also significantly increase RAS-GTP levels in cells and result in complex changes in signaling pathways, positioning them as the most potent SOS1 agonists documented so far.
Article Abstract
Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in ∼30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at submicromolar concentrations, bind to SOS1 with low double-digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314423 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.8b01108 | DOI Listing |
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