Phosphoinositide 3-kinase(PI3Ks)are lipid kinases widely involved in cell proliferation,metastasis and differentiation.Constitutive activation of the PI3K/Akt/mTOR signaling are well confirmed in colorectal cancers(CR...Phosphoinositide 3-kinase(PI3Ks)are lipid kinases widely involved in cell proliferation,metastasis and differentiation.Constitutive activation of the PI3K/Akt/mTOR signaling are well confirmed in colorectal cancers(CRCs).In this study,we identified isopropyl 9-ethyl-1-(naphthalen-1-yl)-9 H-pyrido[3,4-b]indole-3-carboxylate(Z86),as a novel PI3Kαinhibitor with the IC50 value of 4.28μM.The binding of Z86 to PI3Kαwas further confirmed with DARTS and CETSA assay.Immunofluorescence analysis and western blotting data demonstrated that Z86 effectively attenuated PI3K/AKT pathway.Z86 caused dramatic proliferation inhibition of CRCs through G0/G1 cycle arrest rather than apoptosis induction.Besides,the migration of CRCs was also relieved by Z86.The present study not only identified Z86 as a novel PI3Kαinhibitor with potent inhibitory efficiency on PI3K-mediated CRCs growth and migration,but also elucidated a reasonable molecular mechanism of Z86 in the Wnt signaling pathway inhibition.展开更多
基金funded by the National Natural Science Foundation of China(No.32260159,82360725,81960738)the Yunnan Fundamental Research Projects(202301AS070022)+5 种基金Yunnan University(start-up grant to Y.L.and L.K.)the Central Guidance on Local Science and Technology Development Fund of Yunnan Province(202207AB110002)National Key R&D Program of China(2019YFE0109200)the central government guides local science and technology development fund(202207AA110007)the Yunnan Young&Elite Talents Project(YNWR-QNBJ-2020-084)the Youth Innovation Promotion Association CAS(to L.K.).
文摘Phosphoinositide 3-kinase(PI3Ks)are lipid kinases widely involved in cell proliferation,metastasis and differentiation.Constitutive activation of the PI3K/Akt/mTOR signaling are well confirmed in colorectal cancers(CRCs).In this study,we identified isopropyl 9-ethyl-1-(naphthalen-1-yl)-9 H-pyrido[3,4-b]indole-3-carboxylate(Z86),as a novel PI3Kαinhibitor with the IC50 value of 4.28μM.The binding of Z86 to PI3Kαwas further confirmed with DARTS and CETSA assay.Immunofluorescence analysis and western blotting data demonstrated that Z86 effectively attenuated PI3K/AKT pathway.Z86 caused dramatic proliferation inhibition of CRCs through G0/G1 cycle arrest rather than apoptosis induction.Besides,the migration of CRCs was also relieved by Z86.The present study not only identified Z86 as a novel PI3Kαinhibitor with potent inhibitory efficiency on PI3K-mediated CRCs growth and migration,but also elucidated a reasonable molecular mechanism of Z86 in the Wnt signaling pathway inhibition.
