Author:
Nie Shiyun,Chang Lizhong,Huang Ying,Zhou Heyang,Yang Qianqing,Kong Lingmei,Li Yan
Abstract
AbstractPhosphoinositide 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 PI3Kα inhibitor with the IC50 value of 4.28 µM. The binding of Z86 to PI3Kα was 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 PI3Kα inhibitor 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.
Graphical Abstract
Funder
National Natural Science Foundation of China
Yunnan Nationalities University
Applied Basic Research Foundation of Yunnan Province
Central Guidance on Local Science and Technology Development Fund of Yunnan Province
National Key R&D Program of China
central government guides local science and technology development fund
Yunnan Young & Elite Talents Project and the Youth Innovation Promotion Association CAS
Publisher
Springer Science and Business Media LLC
Subject
Organic Chemistry,Plant Science,Pharmacology,Toxicology,Biochemistry,Food Science,Analytical Chemistry