Synthesis and evaluation of novel HER-2 inhibitors to exert anti-breast cancer ability through epithelial-mesenchymal transition (EMT) pathway
- Eur J Med Chem. 2022 Jul 5;237:114325. doi: 10.1016/j.ejmech.2022.114325.
- 1. School of Pharmacy, China Medical University, Shenyang, 110122, PR China; Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, 110004, PR China.
- 2. School of Pharmacy, China Medical University, Shenyang, 110122, PR China.
- 3. Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, 110004, PR China.
- 4. School of Pharmacy, China Medical University, Shenyang, 110122, PR China. Electronic address: [email protected].
Human epidermal growth factor receptor 2 (HER-2) is an essential member of the receptor tyrosine kinase (RTK) superfamily and has been reported as a critical method for treating HER-2 positive breast Cancer. Here, we retained (E)-4-methyl-2-(4-(trifluoromethyl)styryl)oxazole, a fragment of HER-2 inhibitor Mubritinib, and synthesized 32 novel compounds from it. We screened out the most potential compound Q7j with HER-2 positive breast Cancer cells through MTT assays, which possessed low toxicity on normal cells (MCF7-10A). Subsequently, wound healing, transwell, western blotting, and immunofluorescence experiments were performed, and it was found that compound Q7j could suppress cell migration by inhibiting the phosphorylation of HER-2 and affecting the expression of EMT-related proteins. Moreover, the SKBR3 orthotopic xenograft model confirmed that compound Q7j was more effective than Mubritinib in inhibiting the proliferation of Cancer cells. In general, compound Q7j was a potential HER-2 inhibitor in treating breast Cancer, which may be of great significance for developing and improving HER-2 small molecule inhibitors.