期刊
MEDICINAL CHEMISTRY RESEARCH
卷 32, 期 6, 页码 1109-1121出版社
SPRINGER BIRKHAUSER
DOI: 10.1007/s00044-023-03057-3
关键词
PI3K delta; Anticancer; 3D-QSAR; Pharmacophores; ROC analysis; Alveolar lung cancer
PI3K delta signaling is involved in cancer proliferation. In this study, we collected 79 known PI3K delta inhibitors and used them for pharmacophore modeling. Two optimal orthogonal pharmacophores were identified and evaluated using ROC curve analysis. These pharmacophores were then used to search for new anti-PI3K delta hits in the NCI chemical list. In vitro evaluation of the identified compounds showed potential anti-cancer activity, with the most potent hit exhibiting an IC50 value of 4.1 mu M against PI3K delta.
PI3K delta signaling promotes cancer proliferation. To model this interesting target, we collected 79 PI3K delta inhibitors of known bioactivities and divided them into four groups for pharmacophore modelling. Subsequent QSAR modelling (r(64)(2) = 0.82, r(LOO)(2) = 0.86, F = 51.92, and r(PRESS)(2) versus 15 test inhibitors = 0.90) identified two optimal orthogonal pharmacophores that were evaluated using ROC curve analysis. The pharmacophores were subsequently used to mine the National Cancer Institute's (NCI) chemical list for new anti-PI3K delta hits. Subsequent in vitro evaluation identified ten hits of IC50 values ranging from 4.2-51.1 mu M. Seven hits were found to be cytotoxic against A549 alveolar lung cancer cells. The most potent hit exhibited anti-PI3K delta IC50 of 4.1 mu M.
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