基于1,4 - 二芳基 - 1,2,3 - 三唑的脲类化合物作为新型FLT3抑制剂的鉴定与开发
Identification and Development of 1,4-Diaryl-1,2,3-triazolo-Based Ureas as Novel FLT3 Inhibitors.
作者信息
Liu Jisheng, Wang Yuting, Chen Chen, Tu Zhengchao, Zhu Sihua, Zhou Fengtao, Si Hongfei, Zheng Canhui, Zhang Zhang, Cai Qian
机构信息
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou 510632, China.
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
出版信息
ACS Med Chem Lett. 2020 Jul 27;11(8):1567-1572. doi: 10.1021/acsmedchemlett.0c00216. eCollection 2020 Aug 13.
A class of 1,4-diaryl-1,2,3-triazolo-based ureas were synthesized and developed as novel FLT3 inhibitors. The representative compound strongly inhibited FLT3-ITD kinase (IC = 32.8 nM) and isogenic BaF3-FLT3-ITD cell (GI = 0.6 nM). It exhibited potent inhibition against FLT3-ITD positive MV4-11 (GI = 3.0 nM) and MOLM-13 (GI = 5.9 nM) cell lines and high selectivity over FLT3-WT cell lines. It also displayed good pharmacokinetics properties and demonstrated promising oral in vivo efficacy in a MV4-11 cell xenografted mouse model. It might be a potent lead compound for further development to treat FLT3-ITD driven acute myloid leukemia.
合成并开发了一类基于1,4-二芳基-1,2,3-三唑的脲类化合物作为新型FLT3抑制剂。代表性化合物强烈抑制FLT3-ITD激酶（IC = 32.8 nM）和同基因BaF3-FLT3-ITD细胞（GI = 0.6 nM）。它对FLT3-ITD阳性的MV4-11（GI = 3.0 nM）和MOLM-13（GI = 5.9 nM）细胞系表现出强效抑制作用，并且对FLT3-WT细胞系具有高选择性。它还显示出良好的药代动力学性质，并在MV4-11细胞异种移植小鼠模型中证明了有前景的口服体内疗效。它可能是用于进一步开发治疗FLT3-ITD驱动的急性髓性白血病的有效先导化合物。
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