Identification of 2-Aminopyrimidine Derivatives as FLT3 Kinase Inhibitors with High Selectivity over c-KIT,Journal of Medicinal Chemistry

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Identification of 2-Aminopyrimidine Derivatives as FLT3 Kinase Inhibitors with High Selectivity over c-KIT
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-02-09 , DOI: 10.1021/acs.jmedchem.1c01792
Lexian Tong _{1,

2,

3} , Peipei Wang ₄ , Xuemei Li ₁ , Xiaowu Dong _{3,

5,

6} , Xiaobei Hu _{4,

7} , Chang Wang ₄ , Tao Liu ₁ , Jia Li _{4,

7} , Yubo Zhou _{4,

7}

Affiliation

Herein, we report two promising compounds 30 and 36 possessing nanomolar FLT3 inhibitory activities (IC₅₀ = 1.5–7.2 nM), high selectivity over c-KIT (>1000-fold), and excellent anti-AML activity (MV4-11 IC₅₀ = 0.8–3.2 nM). Furthermore, these two compounds efficiently inhibited the growth of multiple mutant BaF3 cells expressing FLT3-ITD, FLT3-D835V/F, FLT3-F691L, FLT3-ITD-F691L, and FLT3-ITD-D835Y. Oral administration of 30 and 36 at 6 mg/kg/d could significantly suppress tumor growth in the MV4-11 cell-inoculated xenograft model, exhibiting tumor growth inhibitory rates of 83.5% and 95.1%, respectively. Importantly, 36 could prolong the mouse survival time in the FLT3-ITD-TKD dual mutation syngeneic mouse model (BaF3-FLT3-ITD-D835Y) at a dose of 6 mg/kg p.o. bid/4W. No clear myelosuppression was observed in the treated group of 36 in the MPO strain of zebrafish, even at 10 μM. In summary, our data demonstrated that 36 may represent a promising candidate for the treatment of FLT3 mutant AML.

中文翻译：

将 2-氨基嘧啶衍生物鉴定为具有比 c-KIT 高选择性的 FLT3 激酶抑制剂

在此，我们报告了两种有前途的化合物30和36 ，它们具有纳摩尔 FLT3 抑制活性 (IC ₅₀ = 1.5–7.2 nM)、比 c-KIT 高选择性 (>1000 倍) 和出色的抗 AML 活性 (MV4-11 IC ₅₀ = 0.8–3.2 nM)。此外，这两种化合物有效抑制了多种表达 FLT3-ITD、FLT3-D835V/F、FLT3-F691L、FLT3-ITD-F691L 和 FLT3-ITD-D835Y 的突变 BaF3 细胞的生长。在 MV4-11 细胞接种异种移植模型中，以 6 mg/kg/d口服给药30和36可显着抑制肿瘤生长，肿瘤生长抑制率分别为 83.5% 和 95.1%。重要的是，36在 6 mg/kg po bid/4W 的剂量下，可延长 FLT3-ITD-TKD 双突变同基因小鼠模型 (BaF3-FLT3-ITD-D835Y) 中的小鼠存活时间。在斑马鱼的 MPO 品系中， 36人的治疗组中没有观察到明显的骨髓抑制，即使在 10 μM 时也是如此。总之，我们的数据表明，36可能代表治疗 FLT3 突变 AML 的有希望的候选者。

更新日期：2022-02-09

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