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 overex-pressed 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.

磷脂酰肌醇-3-激酶的α亚型（PI3Kα）在人类肿瘤中经常发生突变、扩增和过度表达。为了开发针对这种酶的新型抑制剂，我们基于六种PI3Kα选择性化合物进行了药效团模型研究。药效团搜索确定了三种结构新颖的PI3Kα及其H1047R突变体抑制剂。我们的生物学研究表明，我们发现的两种分子抑制了PI3Kα的下游效应物pAKT的形成，并诱导了HCT116结肠癌细胞系的凋亡。基于量子点定位动力学（QPLD）的对接显示，残基Asp933、Glu849、Val851和Gln859似乎是活性抑制剂的关键结合残基。