Identification of a potent 5-phenyl-thiazol-2-ylamine-based inhibitor of FLT3 with activity against drug resistance-conferring point mutations
| Autor: | Kuei Jung Yen, Tsu Hsu, Ling Hui Chou, Yu Ling Huang, Yu-Sheng Chao, H. Eugene Liu, Cheng Tai Lu, Teng Kuang Yeh, Weir-Torn Jiaang, Jen Shin Song, Chun Hwa Chen, Po Chu Kuo, Ching Ping Chen, Shih Chieh Yen, Chiung-Tong Chen, Wen-Hsing Lin, Chen Lung Huang, John T.A. Hsu |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Cell Survival Mutant Mice Nude Antineoplastic Agents Drug resistance Pyrazole Pharmacology Receptor tyrosine kinase Rats Sprague-Dawley Mice Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor hemic and lymphatic diseases Drug Discovery Animals Humans Point Mutation Protein Kinase Inhibitors Cell Proliferation Mice Inbred ICR Dose-Response Relationship Drug Molecular Structure biology Chemistry Point mutation Organic Chemistry Myeloid leukemia Neoplasms Experimental General Medicine Rats Thiazoles fms-Like Tyrosine Kinase 3 Drug Resistance Neoplasm Cell culture biology.protein Drug Screening Assays Antitumor FLT3 Inhibitor |
| Zdroj: | European Journal of Medicinal Chemistry. 100:151-161 |
| ISSN: | 0223-5234 |
| Popis: | Numerous FLT3 inhibitors have been explored as a viable therapy for the treatment of acute myeloid leukemia (AML). However, clinical data have been underwhelming due to incomplete inhibition of FLT3 or the emergence of resistant mutations treated with these older agents. We previously developed a series of 3-phenyl-1H-5-pyrazolylamine derivatives as highly potent and selective FLT3 inhibitors with good in vivo efficacy using an intravenous (IV) route. However, the poor bioavailability of these pyrazole compounds limits the development of these promising antileukemic compounds for clinical use. Herein, we describe a novel class of 5-phenyl-thiazol-2-ylamine compounds that are multi-targeted FLT3 inhibitors. From this class of compounds, compound 7h was very potent against AML cell lines and exhibited excellent oral efficacy in AML xenograft models. In addition, further studies demonstrated that compound 7h exhibited potent in vitro and in vivo activities against clinically relevant AC220 (3)-resistant kinase domain mutants of FLT3-ITD. |
| Databáze: | OpenAIRE |
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