FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of the structure of PCI-32765 (ibrutinib), a BTK kinase inhibitor that was recently reported to bear FLT3 kinase activity through a structure-guided drug design approach, we have discovered compound 18 (CHMFL-FLT3-122), which displayed an IC₅₀ of 40 nM against FLT3 kinase and achieved selectivity over BTK kinase (over 10-fold). It significantly inhibited the proliferation of FLT3-ITD positive AML cancer cell lines MV4-11 (GI₅₀ = 22 nM), MOLM13/14 (GI₅₀ = 21 nM/42 nM). More importantly, 18 demonstrated 170-fold selectivity between FLT3 kinase and c-KIT kinase (GI₅₀ = 11 nM versus 1900 nM) in the TEL-fusion isogenic BaF3 cells indicating a potential to avoid the FLT3/c-KIT dual inhibition induced myelosuppression toxicity. In the cellular context it strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting the cell cycle into the G0/G1 phase. In the in vivo studies 18 demonstrated a good bioavailability (30%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (50 mg/kg) without exhibiting obvious toxicity. Compound 18 might be a potential drug candidate for FLT3-ITD positive AML.

中文翻译：

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（R）-1-（3-（4-氨基-3-（4-苯氧基苯基）-1 H-吡唑并[3,4- d ]嘧啶-1-基）哌啶-1-基）-2-的发现（二甲氨基）乙酮（CHMFL-FLT3-122）作为有效且可口服的FLT3-ITD阳性急性髓细胞白血病的FLT3激酶抑制剂

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。根据最近报道通过结构指导药物设计方法具有FLT3激酶活性的BTK激酶抑制剂PCI-32765（ibrutinib）的结构，我们发现了化合物18（CHMFL-FLT3-122），对FLT3激酶的IC ₅₀为40 nM，相对于BTK激酶具有选择性（超过10倍）。它显着抑制了FLT3-ITD阳性AML癌细胞系MV4-11（GI ₅₀ = 22 nM），MOLM13 / 14（GI ₅₀ = 21 nM / 42 nM）的增殖。更重要的是，有18个在FLT3激酶和c-KIT激酶之间显示出170倍的选择性（GI ₅₀在tel-fusion等基因BaF3细胞中，其相对于1900 nM分别为11 nM和1900 nM），表明有可能避免FLT3 / c-KIT双重抑制诱导的骨髓抑制毒性。在细胞环境中，它通过阻止细胞周期进入G0 / G1期，强烈影响FLT3-ITD介导的信号通路并诱导凋亡。在体内研究中18显示出良好的生物利用度（30％），并在MV4-11细胞接种的异种移植模型（50 mg / kg）中显着抑制了肿瘤的生长，而没有表现出明显的毒性。化合物18可能是FLT3-ITD阳性AML的潜在候选药物。