title: Identification of novel B-RafV600Einhibitors employing FBDD strategy.
abstract: B-Raf kinase is the key point in a main branch of mitogen-activated protein kinase pathways and some of its mutations, such as the V600E mutation, lead to the persistent activation of ERK signaling and the trigger of severe diseases, including melanoma and other somatic cancers. Several potent drugs have been approved to treat B-Raf-related tumors, however, cases of resistance and relapse have been reported universally. Hence, differential scaffolds are in need to alleviate the scarcity of drugs and benefit the therapy of B-Raf-mutant cancers. Herein we report our recent work on the construction of novel B-RafV600Einhibitors employing fragment-based drug design strategy. In this research, we decomposed known inhibitors to fragments and rebuilt new candidates using these blocks according to the evaluation of their potential. Lead compounds were synthesized after selection by means of virtual screening and molecular dynamics validation. Afterwards, we tested the pharmacological efficiency of these entities both in vitro and in vivo utilizing A375 xenograft model. The results favored our rational design intention and hinted this new kind of inhibitors might be helpful in the further explorations of potent agents.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China.
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China.
authors.forename: Han-Yue
authors.initials: HY
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China.
authors.forename: Ze-Feng
authors.initials: ZF
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China.
authors.forename: Yong-Jiao
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China.
authors.forename: Zhong-Chang
authors.initials: ZC
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China; College of Chemical Engineering, Nanjing Forestry University, Nanjing 210073, People's Republic of China.
authors.forename: Dong-Dong
authors.initials: DD
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China. Electronic address: zhuhl@nju.edu.cn.
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf
keywords: B-Raf inhibitor; Chemotherapy; FBDD strategy; Vemurafenib: (PubChem CID: 42611257); Virtual simulation; Xenograft model