P21-activated kinase 1 (PAK1) plays a vital role in the proliferation, survival and migration of cancer cells, which has emerged as a promising drug target for cancer therapy. In this study, a series of 2-indolinone derivatives were designed and synthesized through a structure-based strategy. A potent PAK1 inhibitor (ZMF-005) was discovered, which presented an IC₅₀ value of 0.22 μM against PAK1 with potent antiproliferative activity. Furthermore, we predicted the binding mode of ZMF-005 and PAK1 by molecule docking and dynamic (MD) simulation. In addition, ZMF-005 was documented to induce significant apoptosis and suppress migration in MDA-MB-231 cells. Collectively, these findings revealed that ZMF-005 is a novel potent PAK1 inhibitor for breast cancer treatment.

P21活化激酶1（PAK1）在癌细胞的增殖，存活和迁移中起着至关重要的作用，而癌细胞已成为一种有希望的癌症治疗靶标。在这项研究中，通过基于结构的策略设计和合成了一系列2-吲哚酮衍生物。发现了一种有效的PAK1抑制剂（ZMF-005），它对具有有效抗增殖活性的PAK1的IC ₅₀值为0.22μM。此外，我们通过分子对接和动态（MD）模拟预测了ZMF-005和PAK1的结合模式。另外，据报道ZMF-005在MDA-MB-231细胞中诱导明显的凋亡并抑制迁移。这些发现共同表明ZMF-005 是用于乳腺癌治疗的新型有效PAK1抑制剂。