Publications by authors named "Denis T Akan"
Activating mutations in RAS can lead to oncogenesis by enhancing downstream signaling, such as through the MAPK and PI3K pathways. Therefore, therapeutically targeting RAS may perturb multiple signaling pathways simultaneously. One method for modulating RAS signaling is to target the activity of the guanine nucleotide exchange factor SOS1.
View Article and Find Full Text PDFProteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have proven to be recalcitrant therapeutic targets. One approach for modulating RAS signaling is to target proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1).
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- 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 Synopsis
- Deregulated RAS activity, often due to mutations, is involved in around 30% of human cancers, but effective treatments for RAS-driven tumors are currently lacking.
- A promising strategy involves targeting proteins interacting with RAS, like the guanine nucleotide exchange factor (GEF) SOS1, to modulate RAS activity.
- Research on an indole series of compounds showed that some can effectively activate the nucleotide exchange process and alter signaling in cancer cells, leading to decreased levels of active RAS-GTP and signaling changes in the MAPK-ERK pathway.
Oncogenic mutation of RAS results in aberrant cellular signaling and is responsible for more than 30% of all human tumors. Therefore, pharmacologic modulation of RAS has attracted great interest as a therapeutic strategy. Our laboratory has recently discovered small molecules that activate Son of Sevenless (SOS)-catalyzed nucleotide exchange on RAS and inhibit downstream signaling.
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