Small Molecule SOS1 Agonists Modulate MAPK and PI3K Signaling via Independent Cellular Responses.
ACS Chem Biol
; 14(3): 325-331, 2019 03 15.
Article
en En
| MEDLINE
| ID: mdl-30735352
ABSTRACT
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. Our laboratory has discovered compounds that bind to SOS1 and activate RAS. Interestingly, these SOS1 agonist compounds elicit biphasic modulation of ERK phosphorylation and simultaneous inhibition of AKT phosphorylation levels. Here, we utilized multiple chemically distinct compounds to elucidate whether these effects on MAPK and PI3K signaling by SOS1 agonists were mechanistically linked. In addition, we used CRISPR/Cas9 gene-editing to generate clonally derived SOS1 knockout cells and identified a potent SOS1 agonist that rapidly elicited on-target molecular effects at substantially lower concentrations than those causing off-target effects. Our findings will allow us to further define the on-target utility of SOS1 agonists.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Quinazolinas
/
Bencimidazoles
/
Fosfatidilinositol 3-Quinasas
/
Quinasas de Proteína Quinasa Activadas por Mitógenos
/
Proteína SOS1
/
Indoles
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
ACS Chem Biol
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos