首页|A novel FGFR1 inhibitor CYY292 suppresses tumor progression,invasion,and metastasis of glioblastoma by inhibiting the Akt/GSK3β/snail signaling axis
A novel FGFR1 inhibitor CYY292 suppresses tumor progression,invasion,and metastasis of glioblastoma by inhibiting the Akt/GSK3β/snail signaling axis
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Glioblastoma(GBM)is a malignant brain tumor that grows quickly,spreads widely,and is resistant to treatment.Fibroblast growth factor receptor(FGFR)1 is a receptor tyrosine kinase that regulates cellular processes,including proliferation,survival,migration,and dif-ferentiation.FGFR1 was predominantly expressed in GBM tissues,and FGFR1 expression was negatively correlated with overall survival.We rationally designed a novel small molecule CYY292,which exhibited a strong affinity for the FGFR1 protein in GBM cell lines in vitro.CYY292 also exerted an effect on the conserved Ser777 residue of FGFR1.CYY292 dose-depen-dently inhibited cell proliferation,epithelial-mesenchymal transition,stemness,invasion,and migration in vitro by specifically targeting the FGFR1/AKT/Snail pathways in GBM cells,and this effect was prevented by pharmacological inhibitors and critical gene knockdown.In vivo experiments revealed that CYY292 inhibited U87MG tumor growth more effectively than AZD4547.CYY292 also efficiently reduced GBM cell proliferation and increased survival in orthotopic GBM models.This study further elucidates the function of FGFR1 in the GBM and reveals the effect of CYY292,which targets FGFR1,on downstream signaling pathways directly reducing GBM cell growth,invasion,and metastasis and thus impairing the recruitment,acti-vation,and function of immune cells.
School of Pharmaceutical Science,Wenzhou Medical University,Wenzhou,Zhejiang 325035,China
College of Pharmacy and Research Institute of Drug Development,Chonnam National University,Gwangju 61186,Republic of Korea
Department of Dermatology,Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine,Wenzhou,Zhejiang 325000,China
Zhejiang Lab for Regenerative Medicine,Oujiang Laboratory,Wenzhou,Zhejiang 325035,China
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国家自然科学基金国家自然科学基金国家自然科学基金Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical SciencesScientific Research Project of Wenzhou,Zhejiang,ChinaNational Natural Science Foundation of Zhejiang Province,China
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