2. Academic Validation
  3. Synthesis, biological evaluation and 3D-QSAR study of novel 4,5-dihydro-1H-pyrazole thiazole derivatives as BRAF(V⁶⁰⁰E) inhibitors

Synthesis, biological evaluation and 3D-QSAR study of novel 4,5-dihydro-1H-pyrazole thiazole derivatives as BRAF(V⁶⁰⁰E) inhibitors

  • Bioorg Med Chem. 2015 Jan 1;23(1):46-54. doi: 10.1016/j.bmc.2014.11.029.
Meng-Yue Zhao 1,  Yong Yin 1,  Xiao-Wei Yu 1,  Chetan B Sangani 1,  Shu-Fu Wang 1,  Ai-Min Lu 2,  Li-Fang Yang 3,  Peng-Cheng Lv 1,  Ming-Guo Jiang 3,  Hai-Liang Zhu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
  • 2 College of Science, Nanjing Agriculture University, Nanjing 210095, People's Republic of China.
  • 3 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.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China. Electronic address: zhuhl@nju.edu.cn.
PMID: 25496804 DOI: 10.1016/j.bmc.2014.11.029
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.

Keywords

4,5-Dihydro-1H-pyrazole; Anticancer activity; BRAF(V600E) inhibition; Molecular docking.

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