Discovery and evaluation of 3-phenyl-1H-5-pyrazolylamine-based derivatives as potent, selective and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3) |
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Authors: | Lin Wen-Hsing Hsieh Shu-Yi Yen Shih-Chieh Chen Chiung-Tong Yeh Teng-Kuang Hsu Tsu Lu Cheng-Tai Chen Ching-Ping Chen Chun-Wha Chou Ling-Hui Huang Yu-Lin Cheng An-Huei Chang Yun-I Tseng Ya-Ju Yen Kuei-Rong Chao Yu-Sheng Hsu John T-A Jiaang Weir-Torn |
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Affiliation: | Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli Country 350, Taiwan, ROC. |
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Abstract: | Preclinical investigations and early clinical trial studies suggest that FLT3 inhibitors offer a viable therapy for acute myeloid leukemia. However, early clinical data for direct FLT3 inhibitors provided only modest results because of the failure to fully inhibit FLT3. We have designed and synthesized a novel class of 3-phenyl-1H-5-pyrazolylamine-derived compounds as FLT3 inhibitors which exhibit potent FLT3 inhibition and high selectivity toward different receptor tyrosine kinases. The structure-activity relationships led to the discovery of two series of FLT3 inhibitors, and some potent compounds within these two series exhibited comparable potency to FLT3 inhibitors sorafenib (3) and ABT-869 (4) in both wt-FLT3 enzyme inhibition and FLT3-ITD inhibition on cell growth (MOLM-13 and MV4;11 cells). In particular, the selected compound 12a exhibited the ability to regress tumors in mouse xenograft models using MOLM-13 and MV4;11 cells. |
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