2. Academic Validation
  3. Design, synthesis and anti-cancer activity of pyrrole-imidazole polyamides through target-downregulation of c-kit gene expression

Design, synthesis and anti-cancer activity of pyrrole-imidazole polyamides through target-downregulation of c-kit gene expression

  • Eur J Med Chem. 2020 Dec 1:207:112704. doi: 10.1016/j.ejmech.2020.112704.
Mi Zhang 1,  Jing Liang 1,  Shi-Kun Jiang 1,  Ling Xu 1,  Yan-Ling Wu 2,  Annoor Awadasseid 1,  Xiao-Yin Zhao 1,  Xu-Qiong Xiong 1,  Hiroshi Sugiyama 3,  Wen Zhang 4
Affiliations

Affiliations

  • 1 Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China; Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou, 310014, China.
  • 2 Lab of Molecular Immunology, Virus Inspection Department, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, 310051, China. Electronic address: ylwu@cdc.zj.cn.
  • 3 Lab of Chemical Biology, Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto, 606-8502, Japan. Electronic address: hs@kuchem.kyoto-u.ac.jp.
  • 4 Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China; Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address: wzhang63@zjut.edu.cn.
PMID: 32866755 DOI: 10.1016/j.ejmech.2020.112704
Abstract

Pyrrole-imidazole polyamide (PIP) can specifically bind in the B-DNA minor groove that has been used in several biological applications, such as anti-cancer activity, gene expression and translation control, and visualization of complex genomic areas. c-Kit is a family member of the Tyrosine Kinase (RTK) type III receptor and plays a vital role in tumor growth, proliferation, differentiation, and cell apoptosis; however, its mutations and overexpression induce tumor dysfunction. Here, we designed and synthesized five matched PIPs that can recognize and bind to the DNA sequence in the oncogene c-Kit promoter region, and evaluated their anti-cancer activity. The RTCA assay findings revealed that the PIPs would prevent the proliferation of Cancer cells A549 and SGC-7901. EMSA assay showed that the PIPs were actively interacting with the c-Kit gene target DNA. RT-PCR and Western blot assays have an effect on expression levels of the c-Kit gene in the presence of PIPs. Flow cytometry and wound-healing assays showed that PIPs 4, 5 would cause Apoptosis of Cancer cells and inhibit the migration of cells, respectively. Overall findings indicate that PIP 5 has a relatively significant intracellular and extracellular impact on the target, contributing to migration and proliferation reduction, and Cancer cell Apoptosis. In addition, PIP has a certain ability to evolve into c-Kit gene-targeting drugs.

Keywords

Anti-cancer activity; Apoptosis; Drug; Pyrrole-imidazole polyamide; c-Kit gene.

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