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Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases.

ABSTRACT: The alpha isoform of the phosphatidylinositol-3-kinases (PI3K?) 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 PI3K?-selective compounds. The pharmacophore searching identified three structurally novel inhibitors of PI3K? and its H1047R mutant. Our biological studies show that two of our hit molecules suppressed the formation of pAKT, a downstream effector of PI3K?, 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.

SUBMITTER: Sabbah DA

PROVIDER: S-EPMC4472446 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases.

Sabbah Dima A DA Simms Neka A NA Brattain Michael G MG Vennerstrom Jonathan L JL Zhong Haizhen H

Bioorganic & medicinal chemistry letters 20111213 2

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 PI3K ...[more]

PMID: 22212721

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