Discovery of the novel potent and selective FLT3 inhibitor 1-{5-[7-(3- morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea and its anti-acute myeloid leukemia (AML) activities in vitro and in vivo
| Autor: | Jing-Jing Liu, Li-Jiao Wang, Shengyong Yang, Chun-Hui Zhang, Yong Xu, Yang Lingling, Jiao Yang, Pan Ji, Shan Feng, Zhi-Xing Cao, Ze-Rong Wang, Lei Zhong, Xiaoyan Wang, Yuquan Wei, Ren-Lin Zheng, Heng-Xiu Yan, Shuang Ma, Wei-Wei Li, Qi-Zheng Sun |
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| Rok vydání: | 2012 |
| Předmět: |
Antineoplastic Agents
Pharmacology chemistry.chemical_compound Mice Structure-Activity Relationship In vivo Cell Line Tumor Drug Discovery Thiadiazoles Quinazoline medicine Structure–activity relationship Animals Humans Thiazole Phenylurea Compounds Myeloid leukemia medicine.disease Xenograft Model Antitumor Assays In vitro Leukemia Leukemia Myeloid Acute chemistry fms-Like Tyrosine Kinase 3 Drug Design Quinazolines Molecular Medicine FLT3 Inhibitor |
| Zdroj: | Journal of medicinal chemistry. 55(8) |
| ISSN: | 1520-4804 |
| Popis: | Structure-activity relationship (SAR) studies of 2-(quinazolin-4-ylthio)thiazole derivatives, which are for optimizing the in vitro and in vivo antiacute myeloid leukemia (AML) activity of a previously identified FLT3 inhibitor 2-(6,7-dimethoxyquinazolin-4-ylthio)thiazole (1), are described. SAR studies centering around the head (thiazole) and tails (6- and 7-positions) of the quinazoline moiety of 1 led to the discovery of a series of compounds that exhibited significantly increased potency against FLT3-driven AML MV4-11 cells. Preliminary in vivo assays were carried out on three highly active compounds, whose results showed that 1-{5-[7-(3-morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea (20c) had the highest in vivo activity. Further in vitro and in vivo anti-AML studies were then performed on 20c; in an MV4-11 xenograft mouse model, a once-daily dose of 20c at 100 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analysis were carried out to illustrate the mechanism of action of 20c. |
| Databáze: | OpenAIRE |
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