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.
- 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: [email protected].
- 3. Lab of Chemical Biology, Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto, 606-8502, Japan. Electronic address: [email protected].
- 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: [email protected].
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.