Abstract
BackgroundDevelopment of small-molecule inhibitors targeting phosphoinositide 3-kinase (PI3K) has been an appealing strategy for the treatment of various types of cancers.Methodology/Principal FindingOur approach was to perform structural modification and optimization based on previously identified morpholinoquinoxaline derivative WR1 and piperidinylquinoxaline derivative WR23 with a total of forty-five novel piperazinylquinoxaline derivatives synthesized. Most target compounds showed low micromolar to nanomolar antiproliferative potency against five human cancer cell lines using MTT method. Selected compounds showed potent PI3Kα inhibitory activity in a competitive fluorescent polarization assay, such as compound 22 (IC50 40 nM) and 41 (IC50: 24 nM), which induced apoptosis in PC3 cells. Molecular docking analysis was performed to explore possible binding modes between target compounds and PI3K.Conclusions/SignificanceThe identified novel piperazinylquinoxaline derivatives that showed potent PI3Kα inhibitory activity and cellular antiproliferative potency may be promising agents for potential applications in cancer treatment.
Highlights
The phosphoinositide 3-kinase (PI3K) family includes lipid kinases that catalyze the phosphorylation of the 39-hydroxyl group of phosphatidylinositols to generate second messengers, such as phosphatidylinositol-3,4,5- triphosphate (PIP3) [1,2]
PIP3 recruits downstream effectors along the PI3K/protein kinase B (PKB orAkt)/mammalian target of rapamycin signaling cascade that is of crucial importance for the regulation of cellular growth, survival, and proliferation [3]
Many studies have demonstrated that gain-of-function mutations in the gene encoding the catalytic subunit of PI3Ka, PIK3CA, amplification of PIK3CA, and loss-of-function mutations in PTEN, a lipid phosphatase that dephosphorylates PIP3 result in constitutive activation of the PI3K signaling cascade, which contributes to tumor growth and progression [5,6,7]
Summary
The phosphoinositide 3-kinase (PI3K) family includes lipid kinases that catalyze the phosphorylation of the 39-hydroxyl group of phosphatidylinositols to generate second messengers, such as phosphatidylinositol-3,4,5- triphosphate (PIP3) [1,2]. Many studies have demonstrated that gain-of-function mutations in the gene encoding the catalytic subunit of PI3Ka, PIK3CA, amplification of PIK3CA, and loss-of-function mutations in PTEN, a lipid phosphatase that dephosphorylates PIP3 result in constitutive activation of the PI3K signaling cascade, which contributes to tumor growth and progression [5,6,7]. These observations make targeting PI3Ks, especially PI3Ka, with small-molecule inhibitors a promising strategy for cancer therapy [8,9,10,11]. Development of small-molecule inhibitors targeting phosphoinositide 3-kinase (PI3K) has been an appealing strategy for the treatment of various types of cancers
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