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

Dima A. Sabbah, Neka A. Simms, Michael G. Brattain, Jonathan L Vennerstrom, Haizhen Andrew Zhong

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)876-880
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number2
DOIs
StatePublished - Jan 15 2012

Fingerprint

1-Phosphatidylinositol 4-Kinase
Phosphatidylinositols
Phosphatidylinositol 3-Kinases
Phosphotransferases
Enzyme Inhibitors
Colonic Neoplasms
Tumors
Protein Isoforms
Cells
Apoptosis
Cell Line
Molecules
Enzymes
Neoplasms

Keywords

  • Apoptosis
  • Docking
  • GSK2126458
  • LY294002
  • PI3K
  • Pharmacophore modeling

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases. / Sabbah, Dima A.; Simms, Neka A.; Brattain, Michael G.; Vennerstrom, Jonathan L; Zhong, Haizhen Andrew.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 22, No. 2, 15.01.2012, p. 876-880.

Research output: Contribution to journalArticle

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