This paper describe the structural optimization of a hit compound, N²-(4-(4-methylpiperazin-1-yl)phenyl)-N⁸-phenyl-9H-purine-2,8-diamine (1), which is a reversible kinase inhibitor targeting both EGFR-activating and drug-resistance (T790M) mutations but has poor binding affinity. Structure–activity relationship studies led to the identification of 9-cyclopentyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)-N⁸-phenyl-9H-purine-2,8-diamine (9e) that exhibits significant in vitro antitumor potency against the non-small-cell lung cancer (NSCLC) cell lines HCC827 and H1975, which harbor EGFR-activating and drug-resistance mutations, respectively. Compound 9e was further assessed for potency and selectivity in enzymatic assays and in vivo anti-NSCLC studies. The results indicated that compound 9e is a highly potent kinase inhibitor against both EGFR-activating and resistance mutations and has good kinase spectrum selectivity across the kinome. In vivo, oral administration of compound 9e at a dose of 5 mg/kg caused rapid and complete tumor regression in a HCC827 xenograft model, and an oral dose of 50 mg/kg initiated a considerable antitumor effect in an H1975 xenograft model.

中文翻译：

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N ^2-（4-（4-甲基哌嗪-1-基）苯基）-N ^8-苯基-9 H-嘌呤-2,8-二胺衍生物，一种新型的可逆激酶抑制剂的结构优化和构效关系靶向EGFR激活和耐药突变

本文描述了一种命中化合物N ^2-（4-（4-甲基哌嗪-1-基）苯基）-N ^8-苯基-9 H-嘌呤-2,8-二胺（1）的结构优化。靶向EGFR激活和耐药性（T790M）突变的可逆激酶抑制剂，但结合亲和力较差。结构-活性关系研究导致鉴定出9-环戊基-N ^2-（4-（4-甲基哌嗪-1-基）苯基）-N ^8-苯基-9 H-嘌呤-2,8-二胺（9e）对非小细胞肺癌（NSCLC）细胞系HCC827和H1975表现出显着的体外抗肿瘤能力，分别具有EGFR激活和耐药性突变。在酶促测定和体内抗NSCLC研究中进一步评估了化合物9e的效力和选择性。结果表明，化合物9e是针对EGFR激活和耐药突变的高效激酶抑制剂，并且在整个kinome上具有良好的激酶谱选择性。在体内，在HCC827异种移植模型中以5 mg / kg的剂量口服给予化合物9e可使肿瘤迅速而完全地消退，而在H1975异种移植模型中，口服50 mg / kg的剂量可引发相当大的抗肿瘤作用。