College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, 06974, Republic of Korea.
College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, 06974, Republic of Korea.
Eur J Med Chem. 2021 Apr 15;216:113298. doi: 10.1016/j.ejmech.2021.113298. Epub 2021 Feb 22.
Tumor-associated macrophages (TAMs) are predominantly associated with tumor growth. Colony-stimulating factor 1 receptor (CSF1R) acts as a key regulator of TAM survival and differentiation and is a molecular target for cancer therapies. Herein, novel CSF1R inhibitors were identified through a replacement strategy for the hinge-binding moiety. The introduction of imidazo[1,2-a]pyridine (49) or pyrazolo[1,5-a]pyridine (50) as hinge binders led to 87% and 82% inhibition at 10 nM for CSF1R in the enzymatic assay, with IC values of 25 nM and 27 nM in MNFS60 cells, respectively. These derivatives significantly inhibited CSF1R phosphorylation in cells. Our approach could be utilized as a strategy to discover novel kinase inhibitors.
肿瘤相关巨噬细胞（TAMs）主要与肿瘤生长有关。集落刺激因子 1 受体（CSF1R）是 TAM 存活和分化的关键调节剂，也是癌症治疗的分子靶点。本文通过取代策略鉴定了新型 CSF1R 抑制剂，该策略用于铰链结合部分。在酶测定中，将咪唑并[1,2-a]吡啶（49）或吡唑并[1,5-a]吡啶（50）引入铰链结合物中，可使 CSF1R 的抑制率分别达到 87%和 82%，在 MNFS60 细胞中的 IC 值分别为 25 nM 和 27 nM。这些衍生物可显著抑制细胞中 CSF1R 的磷酸化。我们的方法可用于发现新型激酶抑制剂。
