State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, China.
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, China.
Eur J Med Chem. 2018 Jul 15;155:725-735. doi: 10.1016/j.ejmech.2018.06.043. Epub 2018 Jun 19.
A series of novel selective BRAF 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 BRAF (IC50 = 0.06 μM for BRAF; GI50 = 0.52 μM for A375) over BRAF 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 BRAF and BRAF, pointing out that the future orientation might be seeking for outer space binding of BRAF and avoiding interactions with HIS573 of BRAF. These results brought potent BRAF inhibitors one step further to selective agents, enhancing the potential for safe medication.
我们设计并合成了一系列新型的选择性 BRAF 抑制化合物（化合物 1-16）：5-(2,3-二氢苯并[b][1,4]二恶烷-6-基)-N,3-二芳基-4,5-二氢-1H-吡唑-1-硫代酰胺。评估了它们的抗增殖和 BRAF 抑制活性。虽然化合物 15、4 和 12 与阳性对照药vemurafenib 具有相当的活性，但只有化合物 12 在激酶和细胞水平上对 BRAF（IC50=0.06 μM 用于 BRAF；GI50=0.52 μM 用于 A375）显示出良好的选择性。这一结果符合提高活性和引入选择性的设计理念。流式细胞术分析和 Western blot 证实了细胞凋亡的诱导和激酶抑制活性。对接模拟推断了 BRAF 和 BRAF 的结合模式的差异，指出未来的方向可能是寻找 BRAF 的外部空间结合，避免与 BRAF 的 HIS573 相互作用。这些结果使有效的 BRAF 抑制剂向选择性药物又迈进了一步，提高了安全用药的潜力。
