School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Eur J Med Chem. 2017 Oct 20;139:95-106. doi: 10.1016/j.ejmech.2017.07.074. Epub 2017 Aug 1.
Phosphatidylinositol 3-kinase (PI3K) is a pivotal regulator of intracellular signaling pathways and considered as a promising target in the development of a therapeutic treatment of cancer. Among the different PI3K subtypes, the PIK3CA gene encoding PI3K p110α is frequently mutated and overexpressed in majority of human cancers. Therefore, the inhibition of PI3Kα has been considered to be an efficient approach for the treatment of cancer. In this study, two series compounds containing hydrophilic group in imidazo[1,2-a]pyridine and quinazolin-4(3H)-one were synthesized and their antiproliferative activities against five cancer cell lines, including HCT-116, SK-HEP-1, MDA-MB-231, SNU638 and A549, were evaluated. Compound 1i with most potent antiproliferative activity was selected for further biological evaluation. PI3K kinase assay showed that 1i has selectivity for PI3Kα distinguished from other isoforms. The western blot assay indicated that 1i is more effective than HS-173, an imidazopyridine-based PI3Ka inhibitor, in reducing the levels of phospho-Akt. All these results suggested that 1i is a potent PI3Kα inhibitor and could be considered as a potential candidate for the development of anticancer agents.
磷酸肌醇 3-激酶（PI3K）是细胞内信号通路的关键调节因子，被认为是癌症治疗开发中有前途的靶点。在不同的 PI3K 亚型中，编码 PI3K p110α 的 PIK3CA 基因在大多数人类癌症中频繁发生突变和过表达。因此，抑制 PI3Kα 已被认为是治疗癌症的有效方法。在这项研究中，合成了两个系列的化合物，它们在咪唑并[1,2-a]吡啶和喹唑啉-4(3H)-酮中含有亲水基团，并评估了它们对五种癌细胞系（包括 HCT-116、SK-HEP-1、MDA-MB-231、SNU638 和 A549）的抗增殖活性。具有最强抗增殖活性的化合物 1i 被选为进一步的生物学评估。PI3K 激酶测定表明，1i 对 PI3Kα 具有选择性，与其他同工型区分开来。Western blot 分析表明，1i 在降低磷酸化 Akt 水平方面比基于咪唑并吡啶的 PI3Ka 抑制剂 HS-173 更有效。所有这些结果表明，1i 是一种有效的 PI3Kα 抑制剂，可被视为开发抗癌药物的潜在候选药物。
