Publications by authors named "Jason R Abbott"
Activating mutations in KRAS are the most frequent oncogenic alterations in cancer. The oncogenic hotspot position 12, located at the lip of the switch II pocket, offers a covalent attachment point for KRAS inhibitors. To date, KRAS inhibitors have been discovered by first covalently binding to the cysteine at position 12 and then optimizing pocket binding.
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).
View Article and Find Full Text PDFArticle 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 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.
K-RAS is mutated in approximately 30% of human cancers, resulting in increased RAS signaling and tumor growth. Thus, RAS is a highly validated therapeutic target, especially in tumors of the pancreas, lung and colon. Although directly targeting RAS has proven to be challenging, it may be possible to target other proteins involved in RAS signaling, such as the guanine nucleotide exchange factor Son of Sevenless (SOS).
View Article and Find Full Text PDFA stereoselective synthesis of a fully protected version of the disaccharide unit (2) of incednine (1) is described. The synthesis of 2 proceeds in 4.7% overall yield from commercially available allyl α-d-galactopyranoside over the longest linear sequence.
View Article and Find Full Text PDFA highly stereoselective synthesis of a model C(18)-C(35) spiroketal unit (7) of integramycin has been accomplished via an enantioselective stannyl-crotylboration reaction and an N-iodosuccinimide-mediated spiroketalization of 19a.
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