Discovery, Synthesis, and Evaluation of Highly Selective Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Inhibitor for the Potential Treatment of Metastatic Triple-Negative Breast Cancer

Abstract

We herein report the identification, structural optimization, and structure−activity relationship of thieno[2,3d]pyrimidine derivatives as a novel kind of selective vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors. N-(4-Chloro-3-(trifluoromethyl)phenyl)-4-(6-(4-(4-methylpiperazin-1yl)phenyl)thieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxamide (38k) was the most potent VEGFR3 inhibitor (IC 50 = 110.4 nM) among developed compounds. Compared with VEGFR1 and VEGFR2, VEGFR3 was approximately 100 times more selective. Here, compound 38k significantly inhibited proliferation and migration of VEGF-C-induced human dermal lymphatic endothelial cells (HDLEC), MDA-MB-231, and MDA-MB-436 cells by inactivating the VEGFR3 signaling pathway. Additionally, 38k induced cell apoptosis and a prolonged G1/S-phase in MDA-MB-231 and MDA-MB-436 cells. It also presented acceptable pharmacokinetic characteristics in Sprague-Dawley (SD) rats with an oral bioavailability of 30.9%. In the xenograft model in vivo, 38k effectively inhibited breast cancer growth by suppressing the VEGFR3 signaling pathway. 38k pronouncedly resisted the formation of pulmonary metastatic nodules in mice. Collectively, 38k may be a promising therapeutic agent of metastatic breast cancer.

The Relationship between VEGF-C, TAM, and Lymph Node Metastasis in Oral Cancer

“…It shows that integrated traditional Chinese and Western medicine treatment can improve the immune function of patients with oral cancer, which may improve the therapeutic efficacy. Previous studies have also shown that integrated traditional Chinese and Western medicine treatment improves the therapeutic efficacy of patients with oral cancer, improves the patient's immunity, and brings new hope for the treatment of patients with oral cancer [ 19 , 24 , 25 ]. Traditional Chinese medicine has a very good therapeutic position in the treatment of breast cancer, gastric cancer, and other diseases.…”

Concise synthesis and biological activity evaluation of novel pyrazinyl–aryl urea derivatives against several cancer cell lines, which can especially induce T24 apoptotic and necroptotic cell death

“…The proliferation inhibitory activity of the synthesized pyrazinyl–aryl urea derivatives was assessed using the MTT assay, according to the previous report. 49 Human cancer cell lines including Hep G2, MGC-803, T24, NCI-H460, and PC-3 were purchased from the Typical Culture Preservation Committee Cell Bank of the Chinese Academy of Science (Shanghai, China). Normal bladder epithelial cell line HCV29 was provided by the Department of Cell Biology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine.…”

PTEN regulates invasiveness in pancreatic neuroendocrine tumors through DUSP19-mediated VEGFR3 dephosphorylation

“…Most VEGFR inhibitors are not VEGFR3 selective. However, new ERK inhibitors and highly selective VEGFR3 inhibitors have been developed and are currently under investigation [ 41 , 42 ]. The novel agents may be candidate anti-invasive drugs for treating pNETs.…”