Discovery of 1-(4-(4-Amino-3-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea (CHMFL-FLT3-213) as a Highly Potent Type II FLT3 Kinase Inhibitor Capable of Overcoming a Variety of FLT3 Kinase Mutants in FLT3-ITD Positive AML,Journal of Medicinal Chemistry

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Discovery of 1-(4-(4-Amino-3-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea (CHMFL-FLT3-213) as a Highly Potent Type II FLT3 Kinase Inhibitor Capable of Overcoming a Variety of FLT3 Kinase Mutants in FLT3-ITD Positive AML
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-10-17 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00840
Aoli Wang _{1,

2} , Xixiang Li _{1,

2} , Cheng Chen _{1,

3} , Hong Wu _{1,

2} , Ziping Qi _{1,

2} , Chen Hu _{1,

3} , Kailin Yu _{1,

3} , Jiaxin Wu _{1,

3} , Juan Liu ₄ , Xiaochuan Liu _{1,

2} , Zhenquan Hu _{1,

2} , Wei Wang _{1,

2} , Wenliang Wang _{1,

3} , Wenchao Wang _{1,

2} , Li Wang _{1,

3} , Beilei Wang _{1,

3} , Qingwang Liu ₄ , Lili Li ₅ , Jian Ge ₅ , Tao Ren ₄ , Shanchun Zhang ₆ , Ruixiang Xia ₅ , Jing Liu _{1,

2} , Qingsong Liu _{1,

2,

3,

4}

Affiliation

FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of our previous study that ibrutinib (9) exhibited selective and moderate inhibitory activity against FLT3-ITD positive AML cells, through a structure-guided drug design approach, we have discovered a new type II FLT3 kinase inhibitor, compound 14 (CHMFL-FLT3-213), which exhibited highly potent inhibitory effects against FLT3-ITD mutant and associated oncogenic mutations (including FLT3-D835Y/H/V, FLT3-ITD-D835Y/I/N/A/G/Del, and FLT3-ITD-F691L). In the cellular context 14 strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting cell cycle into G0/G1 phase. In the in vivo studies 14 demonstrated an acceptable bioavailability (F = 19%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (15 mg kg^–1 day^–1, TGI = 97%) without exhibiting obvious toxicity. Compound 14 might be a potential drug candidate for FLT3-ITD positive AML.

中文翻译：

1-（4-（4-氨基-3-（4-（2-吗啉代乙氧基）苯基）-1 H-吡唑并[3,4- d ]嘧啶-1-基）苯基）-3-（5-的发现（叔丁基）异恶唑-3-基）脲（CHMFL-FLT3-213）作为高强度的II型FLT3激酶抑制剂，能够克服FLT3-ITD阳性AML中的各种FLT3激酶突变体

已经在大约30％的AML患者中观察到了FLT3-ITD突变体，并将其作为药物发现靶标进行了广泛的研究。在我们先前的研究中，依鲁替尼（9）对FLT3-ITD阳性AML细胞表现出选择性和中等抑制活性，通过结构指导的药物设计方法，我们发现了一种新型的II型FLT3激酶抑制剂化合物14（CHMFL -FLT3-213），对FLT3-ITD突变体和相关的致癌突变（包括FLT3-D835Y / H / V，FLT3-ITD-D835Y / I / N / A / G / Del和FLT3- ITD-F691L）。在细胞环境中14强烈影响FLT3-ITD介导的信号通路，并通过将细胞周期阻滞到G0 / G1期诱导细胞凋亡。体内研究14在已接种MV4-11细胞的异种移植模型（15 mg kg ^–1天^–1，TGI = 97％）中显示出可接受的生物利用度（F = 19％）并显着抑制了肿瘤的生长，而没有表现出明显的毒性。化合物14可能是FLT3-ITD阳性AML的潜在候选药物。

更新日期：2017-10-17

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