2. Academic Validation
  3. Design and biological evaluation of novel triaryl pyrazoline derivatives with dioxane moiety for selective BRAFV600E inhibition

Design and biological evaluation of novel triaryl pyrazoline derivatives with dioxane moiety for selective BRAFV600E inhibition

  • Eur J Med Chem. 2018 Jul 15:155:725-735. doi: 10.1016/j.ejmech.2018.06.043.
Hong-Lin Li 1,  Mi-Mi Su 1,  Yun-Jie Xu 1,  Chen Xu 2,  Yu-Shun Yang 3,  Hai-Liang Zhu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, China. Electronic address: xuchn@nju.edu.cn.
  • 3 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, China; Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China. Electronic address: ys_yang@nju.edu.cn.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, China; Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China. Electronic address: zhuhl@nju.edu.cn.
PMID: 29940463 DOI: 10.1016/j.ejmech.2018.06.043
Abstract

A series of novel selective BRafV600E inhibitory agents (Compound 1-16) 5-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)-N,3-diaryl-4,5-dihydro-1H-pyrazole-1-carbothioamides have been designed and synthesized. Their anti-proliferation and BRaf inhibitory activities were evaluated. Though 15, 4 and 12 all displayed comparable activity with the positive control Vemurafenib, only 12 indicated fine selectivity on BRafV600E (IC50 = 0.06 μM for BRafV600E; GI50 = 0.52 μM for A375) over BRafWT at both kinase and cell levels. This result satisfied the designing concept of improving activity and introducing selectivity. Flow cytometry analysis and western blot convinced the Apoptosis induction and kinase inhibitory activity. Docking simulation inferred the differences in binding patterns of BRafV600E and BRafWT, pointing out that the future orientation might be seeking for outer space binding of BRafV600E and avoiding interactions with HIS573 of BRafWT. These results brought potent BRaf inhibitors one step further to selective agents, enhancing the potential for safe medication.

Keywords

Antitumor; Apoptosis induction; BRAF(V600E); Dioxane; Selectivity; Triaryl pyrazoline.

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