title: Preclinical Evaluation of a Novel Orally Available SRC/Raf/VEGFR2 Inhibitor, SKLB646, in the Treatment of Triple-Negative Breast Cancer.
abstract: Triple-negative breast cancer (TNBC) is the most aggressive and deadly breast cancer subtype. To date, chemotherapy is the only systemic therapy and prognosis remains poor. Herein, we report the preclinical evaluation of SKLB646 in the treatment of TNBC; SKLB646 is a novel multiple kinase inhibitor developed by us recently. This compound potently inhibited SRC and VEGFR2 with IC50 values of 0.002 μmol/L and 0.012 μmol/L, respectively. It also considerably inhibited B-Raf and C-Raf with IC50 values of 0.022 and 0.019 μmol/L, respectively. It exhibited significant antiproliferation and antiviability activities against TNBC cell lines. Studies of mechanism of action indicated that SKLB646 inhibited the activation of SRC signaling and blocked the MAPK signaling through inhibiting the Raf kinases. Interestingly, SKLB646 dose dependently downregulated the expression of Fra1, a transcriptional factor that plays a critical role in the epithelial-to-mesenchymal transition. In addition, SKLB646 could inhibit HUVEC proliferation, migration, and invasion. It effectively blocked the formation of intersegmental vessels in zebrafish embryos and displayed considerable antiangiogenic effects in the tumor-induced neovascularization zebrafish model. In TNBC xenograft models, SKLB646 suppressed the tumor growth in a dose-dependent manner. Moreover, SKLB646 could remarkably inhibit TNBC cell migration and invasion in vitro. Furthermore, in an experimental lung metastasis model, the overall survival time of groups treated with SKLB646 was much longer compared with the control-, dasatinib-, and paclitaxel-treated groups. In a preliminary pharmacokinetic study, SKLB646 showed good pharmacokinetic properties. Taken together, the preclinical data show that SKLB646 could be a promising lead compound for the treatment of TNBC.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China.
authors.forename: Ming-Wu
authors.initials: MW
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China.
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China.
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China.
authors.forename: Wan-Ting
authors.initials: WT
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China.
authors.forename: Rong-Jie
authors.initials: RJ
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China.
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China.
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China. yangsy@scu.edu.cn.
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases; D048493:Proto-Oncogene Proteins B-raf