2. Academic Validation
  3. Design, synthesis and biological evaluation of 2-indolinone derivatives as PAK1 inhibitors in MDA-MB-231 cells

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.
Dahong Yao 1,  A Ruhan 2,  Jin Jiang 2,  Jian Huang 2,  Jinhui Wang 3,  Weina Han 4
Affiliations

Affiliations

  • 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: wangjinhui@hrbmu.edu.cn.
  • 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: hanweina@163.com.
PMID: 32738980 DOI: 10.1016/j.bmcl.2020.127355
Abstract

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.

Keywords

Apoptosis; Breast cancer; Migration; Molecule docking; PAK1 inhibitor.

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