title: Synthesis, biological evaluation and 3D-QSAR study of novel 4,5-dihydro-1H-pyrazole thiazole derivatives as BRAF(V⁶⁰⁰E) inhibitors.
abstract: Many reports implied that the BRAF serine/threonine kinase was mutated in various types of human tumors, which were related with cell growth, survival and differentiation. To provide new therapeutic opportunities, a series of novel 4,5-dihydro-1H-pyrazole derivatives (6a-10d) containing thiazole moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. All compounds were evaluated in vitro for anticancer activities against WM266.4 human melanoma cell line and breast cancer MCF-7 cell line. Compound 10d displayed the most potential antiproliferative activity with an IC50 value of 0.12μM against cell line WM266.4 and 0.16μM against MCF-7 with positive control Sorafenib. Results of the inhibitory activity against BRAF(V600E) revealed that compound 10d was bearing the best bioactivity with IC50 of 0.05μM as well. On the basis of the result of flow cytometry, with the dose of compound 10d increasing, more and more cancer cell gradually encountered apoptosis or died, which indicated the compound 10d could induce remarkable apoptosis of MCF-7 and WM266.4 cells in a dose dependent manner. Furthermore, docking simulation of inhibitor analogues and 3D-QSAR modeling provided potential binding model and further knowledge of pharmacophore.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Meng-Yue
authors.initials: MY
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Chetan B
authors.initials: CB
authors.lastname: Sangani
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Shu-Fu
authors.initials: SF
authors.lastname: Wang
authors.affiliation: College of Science, Nanjing Agriculture University, Nanjing 210095, People's Republic of China.
authors.forename: Ai-Min
authors.initials: AM
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China; Guangxi Colleges and Universities Key Laboratory of Utilization of Microbial and Botanical Resources, Guangxi University for Nationalities, 530006, People's Republic of China.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Peng-Cheng
authors.initials: PC
authors.lastname: Lv
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China; Guangxi Colleges and Universities Key Laboratory of Utilization of Microbial and Botanical Resources, Guangxi University for Nationalities, 530006, People's Republic of China.
authors.forename: Ming-Guo
authors.initials: MG
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China. Electronic address: zhuhl@nju.edu.cn.
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013844:Thiazoles; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: 4,5-Dihydro-1H-pyrazole; Anticancer activity; BRAF(V600E) inhibition; Molecular docking