Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Design and Synthesis of Novel Nordihydroguaiaretic Acid (NDGA) Analogues as Potential FGFR1 Kinase Inhibitors With Anti-Gastric Activity and Chemosensitizing Effect
Ist Teil von
Frontiers in pharmacology, 2020-09, Vol.11, p.518068-518068
Ort / Verlag
Frontiers Media S.A
Erscheinungsjahr
2020
Quelle
EZB Free E-Journals
Beschreibungen/Notizen
Aberrant fibroblast growth factor receptor-1 (FGFR1), a key driver promoting gastric cancer (GC) progression and chemo-resistance, has been increasingly recognized as a potential therapeutic target in GC. Hereon, we designed and synthesized a series of asymmetric analogues using
Af23
and NDGA as lead compounds by retaining the basic structural framework (bisaryl-1,4-dien-3-one) and the unilateral active functional groups (3,4-dihydroxyl). Thereinto,
Y14
showed considerable inhibitory activity against FGFR1. Next, pharmacological experiments showed that
Y14
could significantly inhibit the phosphorylation of FGFR1 and its downstream kinase AKT and ERK, thus inhibiting the growth, survival, and migration of gastric cancer cells. Furthermore, compared with 5-FU treatment alone, the combination of
Y14
and 5-FU significantly reduced the phosphorylation level of FGFR1, and enhanced the anti-cancer effect by inhibiting the viability and colony formation in two gastric cancer cell lines. These results confirmed that
Y14
exerted anti-gastric activity and chemosensitizing effect by inhibiting FGFR1 phosphorylation and its downstream signaling pathway
in vitro
. This work also provides evidence that
Y14
, an effective FGFR1 inhibitor, could be used alone or in combination with chemotherapy to treat gastric cancer in the future.