Inhibition of protein kinases is a validated concept for pharmacological intervention in cancers. Many kinase inhibitors have been approved for clinical use, but their practical application is often limited. Here, we describe a collection of 23 novel 2,6,9-trisubstituted purine derivatives with nanomolar inhibitory activities against PDGFRα, a receptor tyrosine kinase often found constitutively activated in various tumours. The compounds demonstrated strong and selective cytotoxicity in the human eosinophilic leukemia cell line EOL-1, whereas several other cell lines were substantially less sensitive. The cytotoxicity in EOL-1, which is known to express the FIP1L1‐PDGFRA fusion gene encoding an oncogenic kinase, correlated significantly with PDGFRα inhibition. EOL-1 cells treated with the compounds also exhibited dose-dependent inhibition of PDGFRα autophosphorylation and suppression of its downstream signaling pathways with concomitant G₁ phase arrest, confirming the proposed mechanism of action. Our results show that substituted purines can be used as platforms for preparing tyrosine kinase inhibitors with specific activity towards eosinophilic leukemia.

抑制蛋白激酶是在癌症中进行药理干预的经过验证的概念。许多激酶抑制剂已被批准用于临床，但其实际应用常常受到限制。在这里，我们描述了23种新颖的2,6,9-三取代嘌呤衍生物的集合，这些衍生物具有针对PDGFRα的纳摩尔抑制活性，PDGFRα是一种经常在各种肿瘤中被组成性激活的受体酪氨酸激酶。该化合物在人嗜酸性粒细胞白血病细胞株EOL-1中表现出强而有选择性的细胞毒性，而其他几种细胞株的敏感性大大降低。EOL-1中的细胞毒性，已知表达FIP1L1-PDGFRA编码致癌激酶的融合基因与PDGFRα抑制作用显着相关。用该化合物处理的EOL-1细胞还表现出剂量依赖性的PDGFRα自磷酸化抑制作用，并抑制其下游信号通路并伴有G ₁期阻滞，从而证实了所提出的作用机理。我们的结果表明，取代的嘌呤可用作制备对嗜酸性粒细胞白血病具有特异活性的酪氨酸激酶抑制剂的平台。