Quinoxalinhydrazide Pharmacophore Based identification of Novel Anticancer Compounds

Quinoxalinehydrazides represent a novel class of compounds with excellent potency in a panel of cancer cell lines. Recently, we have discovered a prototype compound, SC144, which showed significant in vivo efficacy in mice xenograft models of human breast cancer cells. The subsequent structure–activity relationship study resulted in the discovery of SC161 with better potency in cancer cell lines.1 Further exploring the possible conformational space by a 10 ns molecular dynamics simulation resulted in various pharmacophore orientations. The trajectory analysis indicated that in most of the simulation time, the molecule stays favorably in a compact planar-like orientation (Figure 1). We therefore built a pharmacophore model based on the cluster containing the highest number of frames to represent the most probable orientation.2,3 The model was used to screen a subset of our small molecule database containing 350,000 compounds. 35 compounds were selected for the initial cytotoxicity screen. Seventeen compounds belonging to oxadiazolopyrazine and quinoline class displayed cytotoxicity in various cancer cell lines. Five of them, all bearing an oxadiazolopyrazine scaffold, showed IC50 values <3 m in several tumor cell lines. The most potent compound, I, showed IC50 values <2 um in three cancer cell lines. This study shows that conformational sampling of a lead small molecule followed by representative pharmacophore model development is an efficient approach for the rational design of novel biologically active agents with similar or better potency than the original lead but with different physicochemical properties.