Virtual screening, SAR and discovery of 5-(indole-3-yl)-2-[(2-nitrophenyl)amino] [1,3,4]-oxadiazole as a novel Bcl-2 inhibitor.
2017
A new series of oxadiazoles were designed to act as inhibitors of the anti-apoptotic Bcl-2
protein. Virtual screening led to the discovery of new hits that interact with Bcl-2 at the BH3
binding pocket. Further study of the structure-activity relationship of the most active
compound of the first series, compound 1, led to the discovery of a novel oxadiazole
analogue, compound 16j, that was a more potent small molecule inhibitor of Bcl-2. 16j had
good in vitro inhibitory activity with sub-micromolar IC50 values in a metastatic human
breast cancer cell line (MDA-MB-231) and a human cervical cancer cell line (HeLa). The
antitumour effect of 16j is concomitant with its ability to bind to Bcl-2 protein as shown by
an enzyme linked immunosorbent assay (IC50 = 4.27 μM). Compound 16j has a great
potential to develop into highly active anticancer agent.
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