Design, synthesis and biological evaluation of 2-indolinone derivatives as PAK1 inhibitors in MDA-MB-231 cells
- Bioorg Med Chem Lett. 2020 Sep 1;30(17):127355. doi: 10.1016/j.bmcl.2020.127355.
- 1. Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Baojian Road 157, Nangang District, Harbin 150081, PR China; School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen 518118, PR China; School of Pharmaceutical Sciences, Shenzhen university, Shenzhen 518118, PR China.
- 2. Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Baojian Road 157, Nangang District, Harbin 150081, PR China.
- 3. Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Baojian Road 157, Nangang District, Harbin 150081, PR China. Electronic address: [email protected].
- 4. Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Baojian Road 157, Nangang District, Harbin 150081, PR China. Electronic address: [email protected].
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.