Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research (J.-l.L., X.Z., C.-l.G., X.W., L-j.T., J.D., L-h.M.) and Department of Medicinal Chemistry (W-h.D.), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China; and School of Pharmacy, East China University of Science and Technology, Shanghai, P.R. China (G.-r.G., S.-f.C. W.-h.D.).
J Pharmacol Exp Ther. 2014 Mar;348(3):432-41. doi: 10.1124/jpet.113.210724. Epub 2013 Dec 20.
Phosphatidylinositol 3-kinase, α isoform (PI3Kα) plays essential roles in cell metabolism, growth, and proliferation and has been validated as a promising anticancer target. In an effort to search for new PI3Kα-selective inhibitors, DW series compounds were designed and synthesized aiming to reduce the off-target effects of their parent compound PIK-75 [2-methyl-5-nitro-1-benzenesulfonic acid 2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazide], which was reported to selectively target PI3Kα. A series of compounds named DW series potently inhibited the kinase activity of PI3Kα with little activity against PI3K-related protein kinases and a panel of 15 tyrosine kinases. Similar to PIK-75, DW series compounds were more potent to inhibit PI3Kα among four class I PI3K isoforms, whereas a representative compound DW09849 [(E)-N'-((6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-N-ethyl-2-methyl-5-nitrobenzohydrazide] displayed distinct binding mode compared with PIK-75. Although DW series compounds inhibited proliferation of rhabdomyosarcoma RH30 cells at elevated 50% inhibitory concentrations (IC50) in comparison with PIK-75, they were more selective than PIK-75 to inhibit PI3K signaling in the cellular context. In particular, DW09849 significantly and persistently blocked PI3K/protein kinase B signaling in RH30 cells, which consequently arrested RH30 cells in the G1 phase. Moreover, DW09849 selectively suppressed the proliferation and clonogenesis of transformed RK3E/HR cells harboring oncogenic mutation of p110α H1047R, as well as a panel of human breast cancer cells containing mutated PI3Kα, which is consistent with the finding that DW09849 demonstrated preference against H1047R mutated PI3Kα in molecular docking stimulation. These results suggest that DW series compounds, especially DW09849, selectively targeting PI3Kα with less off-target effects than PIK-75, provide new clues for the design and discovery of new specific PI3Kα inhibitors for cancer therapy.
磷脂酰肌醇 3-激酶，α 异构体（PI3Kα）在细胞代谢、生长和增殖中发挥着重要作用，已被验证为一种有前途的抗癌靶点。为了寻找新的 PI3Kα 选择性抑制剂，设计并合成了 DW 系列化合物，旨在降低其母体化合物 PIK-75（2-甲基-5-硝基-1-苯磺酸 2-[(6-溴咪唑并[1,2-a]吡啶-3-基)亚甲基]-1-甲基酰肼）的脱靶效应，PIK-75 被报道选择性靶向 PI3Kα。一系列名为 DW 系列的化合物强烈抑制 PI3Kα 的激酶活性，对 PI3K 相关蛋白激酶和 15 种酪氨酸激酶的活性很小。与 PIK-75 相似，DW 系列化合物在四种 I 类 PI3K 同工型中对 PI3Kα 的抑制作用更强，而代表性化合物 DW09849 [(E)-N'-((6-溴咪唑并[1,2-a]吡啶-3-基)亚甲基)-N-乙基-2-甲基-5-硝基苯甲酰肼]与 PIK-75 相比表现出明显不同的结合模式。尽管 DW 系列化合物在比较高的 50%抑制浓度（IC50）下抑制横纹肌肉瘤 RH30 细胞的增殖，但与 PIK-75 相比，它们对细胞内 PI3K 信号的抑制更具选择性。特别是，DW09849 显著并持续阻断 RH30 细胞中的 PI3K/蛋白激酶 B 信号，从而将 RH30 细胞阻滞在 G1 期。此外，DW09849 选择性抑制携带 p110α H1047R 致癌突变的转化 RK3E/HR 细胞以及一组含有突变 PI3Kα 的人乳腺癌细胞的增殖和克隆形成，这与 DW09849 在分子对接刺激中表现出对 H1047R 突变 PI3Kα 的偏好一致。这些结果表明，DW 系列化合物，特别是 DW09849，选择性靶向 PI3Kα，脱靶效应小于 PIK-75，为设计和发现新的特异性 PI3Kα 抑制剂用于癌症治疗提供了新的线索。
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