Design and synthesis 1H-Pyrrolo[2,3-b]pyridine derivatives as FLT3 inhibitors for the treatment of Acute myeloid Leukemia.
Design and synthesis 1H-Pyrrolo[2,3-b]pyridine derivatives as FLT3 inhibitors for the treatment of Acute myeloid Leukemia.
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DOI：
10.1016/j.bmc.2024.117631
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发表时间：
2024-02
影响因子：
3.5
通讯作者：
Tian-Hua Wei;Yun Zhou;Jin Yang;Meng-Yuan Zhang;Jing-Jing Wang-Jing;Zhen Tong;J Wu;Yi-Bo Wang;Jiu-Kai Sha;Min Chen;Ning Ding;Yan-cheng Yu;Weichen Dai;Xue-jiao Leng;Xin Xue;Shan-Liang Sun;Xiao-long Wang;Nianyu Li;Zhi‐Hao Shi
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作者：
Tian-Hua Wei;Yun Zhou;Jin Yang;Meng-Yuan Zhang;Jing-Jing Wang-Jing;Zhen Tong;J Wu;Yi-Bo Wang;Jiu-Kai Sha;Min Chen;Ning Ding;Yan-cheng Yu;Weichen Dai;Xue-jiao Leng;Xin Xue;Shan-Liang Sun;Xiao-long Wang;Nianyu Li;Zhi‐Hao Shi
急性髓性白血病（AML）是最常见的血癌类型，与fms样酪氨酸激酶3 （FLT3）的过表达密切相关，FLT3是III类受体酪氨酸激酶家族的成员。随着FLT3内部串联重复改变（ITD）和酪氨酸激酶结构域（TKD）突变的出现，开发FLT3小分子抑制剂已成为治疗AML的有效药物化学策略。在此，我们设计并合成了两个系列的1h -吡咯[2,3-b]吡啶衍生物cm1 - cm24，作为基于f14的FLT3抑制剂，我们之前报道过，可以靶向FLT3的疏水性后袋。在这些衍生物中，cm5对FLT3和FLT3- itd表现出显著的抑制作用，在浓度为1 μΜ时，抑制率分别为57.72%和53.77%。此外，cm5对flt3依赖性的人AML细胞株MOLM-13和MV4-11（均携带FLT3-ITD突变体）表现出有效的抑制作用，ic50值分别为0.75 μM和0.64 μM。在我们的细胞机制研究中，cm5还通过在G0/G1期阻止细胞周期进展有效地诱导细胞凋亡。此外，在计算模拟研究的基础上，详细讨论了酰胺和尿素连接函数。cm5将作为一种新的先导化合物，用于进一步结构修饰和开发FLT3抑制剂，特异性靶向FLT3- itd突变的AML。
Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivativesCM1–CM24, as FLT3 inhibitors based onF14, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates,CM5showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 μΜ. Furthermore,CM5demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3-ITD mutant), with IC50values of 0.75 μM and 0.64 μM respectively. In our cellular mechanistic studies,CM5also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies.CM5will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3-ITD mutations.