Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases
Copyright policy )Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases
The alpha isoform of the phosphatidylinositol-3-kinases (PI3Kα) is often mutated, amplified and overexpressed in human tumors. In an effort to develop new inhibitors targeting this enzyme, we carried out a pharmacophore model study based on six PI3Kα-selective compounds. The pharmacophore searching identified three structurally novel inhibitors of PI3Kα and its H1047R mutant. Our biological studies show that two of our hit molecules suppressed the formation of pAKT, a downstream effector of PI3Kα, and induced apoptosis in the HCT116 colon cancer cell line. QPLD-based docking showed that residues Asp933, Glu849, Val851, and Gln859 appeared to be key binding residues for active inhibitors.
- Nebraska Medical Center United States
- University of Nebraska at Omaha United States
- University of Nebraska Medical Center United States
Models, Molecular, Dose-Response Relationship, Drug, Molecular Structure, Antineoplastic Agents, Apoptosis, Stereoisomerism, Phosphatidylinositol 3-Kinases, Structure-Activity Relationship, Cell Line, Tumor, Colonic Neoplasms, Humans, Drug Screening Assays, Antitumor, Protein Kinase Inhibitors, Phosphoinositide-3 Kinase Inhibitors
Models, Molecular, Dose-Response Relationship, Drug, Molecular Structure, Antineoplastic Agents, Apoptosis, Stereoisomerism, Phosphatidylinositol 3-Kinases, Structure-Activity Relationship, Cell Line, Tumor, Colonic Neoplasms, Humans, Drug Screening Assays, Antitumor, Protein Kinase Inhibitors, Phosphoinositide-3 Kinase Inhibitors
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