State Key Laboratory of Respiratory Diseases , Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue , Guangzhou 510530 , China.
University of Chinese Academy of Sciences , 19 Yuquan Road , Beijing 100049 , China.
J Med Chem. 2018 Mar 22;61(6):2353-2371. doi: 10.1021/acs.jmedchem.7b01612. Epub 2018 Mar 13.
Colony stimulating factor 1 receptor kinase (CSF1R) is a well validated molecular target for anticancer drug discovery. Herein, we report the design, synthesis, and structure-activity relationship study of 2-oxo-3,4-dihydropyrimido[4,5- d]pyrimidines as new orally bioavailable CSF1R inhibitors. One of the most promising compounds, 3bw, potently inhibits CSF1R kinase with an IC value of 3.0 nM, while it is less potent against structurally related epidermal growth factor receptor (EGFR) and other kinases. The kinase inhibition of 3bw was further validated by Western blotting analysis in RAW264.7 macrophages. The molecule also potently blocks macrophage infiltration, abrogates the protumorigenic influences of macrophages, and exhibits reasonable pharmacokinetic profile. Compound 3bw may serve as a new valuable lead compound for future anticancer drug discovery.
集落刺激因子 1 受体激酶（CSF1R）是癌症药物发现中经过充分验证的分子靶点。本文报道了 2-氧代-3,4-二氢嘧啶并[4,5-d]嘧啶作为新型口服生物可用 CSF1R 抑制剂的设计、合成和构效关系研究。其中最有前途的化合物 3bw 对 CSF1R 激酶具有很强的抑制作用，IC 值为 3.0 nM，而对结构相关的表皮生长因子受体（EGFR）和其他激酶的抑制作用较弱。在 RAW264.7 巨噬细胞中通过 Western blot 分析进一步验证了 3bw 的激酶抑制作用。该分子还能强烈抑制巨噬细胞浸润，消除巨噬细胞的促肿瘤影响，并具有合理的药代动力学特征。化合物 3bw 可能成为未来癌症药物发现的有价值的新先导化合物。
