Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, PR China; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, PR China.
Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, PR China; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, PR China.
Eur J Med Chem. 2023 Mar 15;250:115192. doi: 10.1016/j.ejmech.2023.115192. Epub 2023 Feb 9.
To search for novel medicines for intervention of triple-negative breast cancer (TNBC), a series of phenylsulfonyl furoxan-based 2,4-diaminopyrimidine derivatives (8a-t) were designed and synthesized based on blocking FAK-mediated signaling pathways through both kinase-dependent and -independent manners. The most active compound 8f not only significantly inhibited FAK kinase activity (IC = 27.44 nM), displayed potent inhibitory effects on the proliferation (IC = 0.126 μM), invasion and migration of MDA-MB-231 cells, superior to the most widely studied FAK inhibitor, TAE226, bearing 2,4-diaminopyrimidine, but also released high levels of NO, contributing to blockage of FAK mediated-signaling pathways by upregulating of p53 as well as suppressing the Y397 phosphorylation and its downstream effectors, including p-Akt, MMP-2, and MMP-9 via kinase-independent manner, leading to apoptosis induction and decrease of FAs and SFs in TNBC cells. Importantly, 8f inhibited the lung metastasis of TNBC in vivo. Together, 8f may serve as a promising candidate for the treatment of metastatic TNBC.
为了寻找干预三阴性乳腺癌（TNBC）的新型药物，我们基于通过激酶依赖性和非依赖性方式阻断 FAK 介导的信号通路，设计并合成了一系列基于苯磺酰基呋喃甲酰基的 2,4-二氨基嘧啶衍生物（8a-t）。最活跃的化合物 8f 不仅显著抑制了 FAK 激酶活性（IC = 27.44 nM），对 MDA-MB-231 细胞的增殖（IC = 0.126 μM）、侵袭和迁移具有很强的抑制作用，优于最广泛研究的 FAK 抑制剂 TAE226，后者含有 2,4-二氨基嘧啶，但也释放出高水平的 NO，通过上调 p53 以及抑制 Y397 磷酸化及其下游效应物（包括 p-Akt、MMP-2 和 MMP-9）来阻断 FAK 介导的信号通路，从而导致 TNBC 细胞凋亡诱导和 FAs 和 SFs 的减少。重要的是，8f 抑制了 TNBC 的体内肺转移。总之，8f 可能是治疗转移性 TNBC 的一种很有前途的候选药物。
