鉴定 2-氨基嘧啶衍生物作为 FLT3 激酶抑制剂，对 c-KIT 具有高选择性。
Identification of 2-Aminopyrimidine Derivatives as FLT3 Kinase Inhibitors with High Selectivity over c-KIT.
机构信息
ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
School of Materials Science and Engineering, Zhejiang University, Hangzhou 310027, P. R. China.
出版信息
J Med Chem. 2022 Feb 24;65(4):3229-3248. doi: 10.1021/acs.jmedchem.1c01792. Epub 2022 Feb 9.
Herein, we report two promising compounds and possessing nanomolar FLT3 inhibitory activities (IC = 1.5-7.2 nM), high selectivity over c-KIT (>1000-fold), and excellent anti-AML activity (MV4-11 IC = 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 and 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, 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 in the MPO strain of zebrafish, even at 10 μM. In summary, our data demonstrated that may represent a promising candidate for the treatment of FLT3 mutant AML.
本文报道了两种具有前景的化合物 和 ，它们对 FLT3 具有纳摩尔级的抑制活性（IC = 1.5-7.2 nM），对 c-KIT 的选择性高（>1000 倍），对 AML 具有优异的抑制活性（MV4-11 IC = 0.8-3.2 nM）。此外，这两种化合物能有效抑制表达 FLT3-ITD、FLT3-D835V/F、FLT3-F691L、FLT3-ITD-F691L 和 FLT3-ITD-D835Y 的多种突变型 BaF3 细胞的生长。化合物 和 以 6 mg/kg/d 的剂量口服给药，能显著抑制 MV4-11 细胞接种的异种移植模型中的肿瘤生长，抑制率分别为 83.5%和 95.1%。重要的是，化合物 以 6 mg/kg 剂量口服、bid/4W 给药，能延长 FLT3-ITD-TKD 双突变同基因小鼠模型（BaF3-FLT3-ITD-D835Y）中荷瘤小鼠的存活时间。在 MPO 品系斑马鱼中，化合物 治疗组未观察到明显的骨髓抑制，即使在 10 μM 时也没有。总之，我们的数据表明，化合物 可能是治疗 FLT3 突变型 AML 的一种有前途的候选药物。
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