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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Sabbah, Dima A.²  Simms, Neka A.³  Brattain, Michael G.³  Vennerstrom, Jonathan L.²  Zhong, Haizhen¹ 

[1] Univ Nebraska, Dept Chem, Omaha, NE 68182 USA

[2] Univ Nebraska Med Ctr, Coll Pharm, Nebraska Med Ctr 986025, Omaha, NE 68198 USA

[3] Univ Nebraska Med Ctr, Eppley Canc Inst, Nebraska Med Ctr 985920, Omaha, NE 68198 USA

关键词: PI3K;    Docking;    Pharmacophore modeling;    Apoptosis;    LY294002;    GSK2126458;   

DOI  :  10.1016/j.bmcl.2011.12.044

来源: Elsevier

【 摘 要 】

The alpha isoform of the phosphatidylinositol-3-kinases (PI3K alpha) 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 alpha-selective compounds. The pharmacophore searching identified three structurally novel inhibitors of PI3K alpha and its H1047R mutant. Our biological studies show that two of our hit molecules suppressed the formation of pAKT, a downstream effector of PI3K alpha, and induced apoptosis in the HCT116 colon cancer cell line. QPLD-based docking showed that residues Asp933, G1u849, Va1851, and Gln859 appeared to be key binding residues for active inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.

【 授权许可】

Free