Synthesis and biological evaluation of 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine covalent inhibitors as potential agents for the treatment of acute myeloid leukemia
Synthesis and biological evaluation of 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine covalent inhibitors as potential agents for the treatment of acute myeloid leukemia
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DOI：
10.1016/j.bmc.2022.116937
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Liang C
中科院分区：
文献类型：
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作者：
Ji-Bo Kang;Lu Chen;Xue-Jiao Leng;Jing-Jing Wang;Yang Cheng;Shi-Han Wu;Yi-Yuan Ma;Li-Jin Yang;Yu-Hao Cao;Xiao Yang;Zhen-Jiang Tong;Jia-Zhen Wu;Yi-Bo Wang;Hai Zhou;Jia-Chuan Liu;Ning Ding;Wei-Chen Dai;Yan-Cheng Yu;Xin Xue;Shan-Liang Sun;Xiao-Bin Dai;Liang C
• A series of 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b pyridin-3-amine derivatives as FLT3 covalent inhibitors were designed and synthesized. • Compound C14 was potent to inhibit FLT3 (IC 50 = 256 nM) and had strong inhibitory activity against the human AML cell lines MOLM-13 (IC 50 = 507 nM) as well as MV4-11 (IC 50 = 325 nM). • We explored the mechanism of FLT3 inhibitory activity of compound C14 and used molecular docking to further corroborate the enzyme inhibition mechanism. • Compound C14 could be a promising agent for further developing therapeutic remedy for AML. Fms-like tyrosine kinase 3 (FLT3) mutation has been strongly associated with increased risk of relapse, and the irreversible covalent FLT3 inhibitors had the potential to overcome the drug-resistance. In this study, a series of simplified 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b pyridin-3-amine derivatives containing two types of Michael acceptors (vinyl sulfonamide, acrylamide) were conveniently synthesized to target FLT3 and its internal tandem duplications (ITD) mutants irreversibly. The kinase inhibitory activities showed that compound C14 displayed potent inhibition activities against FLT3 (IC 50 = 256 nM) and FLT3-ITD by 73% and 25.34% respectively, at the concentration of 1 μM. The antitumor activities indicated that C14 had strong inhibitory activity against the human acute myeloid leukemia (AML) cell lines MOLM-13 (IC 50 = 507 nM) harboring FLT3-ITD mutant, as well as MV4-11 (IC 50 = 325 nM) bearing FLT3-ITD mutation. The biochemical analyses showed that these effects were related to the ability of C14 to inhibit FLT3 signal pathways, and C14 could induce apoptosis in MV4-11 cell as demonstrated by flow cytometry. Fortunately, C14 showed very weak potency against FLT3-independent human cervical cancer cell line HL-60 (IC 50 > 10 μM), indicating that it might have no off-target toxic effects. In light of these data, compound C14 represents a novel covalent FLT3 kinase inhibitor for targeted therapy of AML.
