含有 3,4,5-三甲氧基苯基结构的查耳酮能够选择性抑制致癌性 K-Ras 信号。
Chalcones bearing a 3,4,5-trimethoxyphenyl motif are capable of selectively inhibiting oncogenic K-Ras signaling.
机构信息
Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH 45435, USA.
Department of Chemistry, Wright State University, Dayton, OH 45435, USA.
出版信息
Bioorg Med Chem Lett. 2020 Jun 1;30(11):127144. doi: 10.1016/j.bmcl.2020.127144. Epub 2020 Mar 28.
Ras proteins are small GTPases which regulate cellular proliferation, differentiation, and apoptosis. Constitutively active mutant Ras are expressed in ~15-20% human cancers, and K-Ras mutations account for ~85% of all Ras mutations. Despite the significance of Ras proteins in refractory cancers, there is no anti-Ras drug available in clinic. Since K-Ras must interact with the plasma membrane (PM) for biological activity, inhibition of the K-Ras/PM interaction is a tractable approach to block oncogenic K-Ras activity. Here, we discovered chalcones 1 and 8 exhibit anti-K-Ras activity, and show that the compounds mislocalize K-Ras from the PM and block oncogenic K-Ras signal output. Also, 1 inhibits the growth of K-Ras-driven human cancer cells. Our data suggest that 1 could be a promising starting point for developing anti-K-Ras cancer drug.
Ras 蛋白是一种小 GTP 酶，可调节细胞增殖、分化和凋亡。约 15-20%的人类癌症中表达组成性激活的突变 Ras，而 K-Ras 突变占所有 Ras 突变的~85%。尽管 Ras 蛋白在难治性癌症中具有重要意义，但临床上尚无抗 Ras 药物。由于 K-Ras 必须与质膜 (PM) 相互作用才能发挥生物活性，因此抑制 K-Ras/PM 相互作用是阻断致癌 K-Ras 活性的可行方法。在这里，我们发现查耳酮 1 和 8 具有抗 K-Ras 活性，并表明这些化合物将 K-Ras 从 PM 错误定位并阻断致癌 K-Ras 信号输出。此外，1 抑制 K-Ras 驱动的人类癌细胞的生长。我们的数据表明，1 可能是开发抗 K-Ras 癌症药物的有前途的起点。
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