Structural Optimization and Structure鈥揂ctivity Relationships of N2-(4-(4-Methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine Derivatives, a New Clas

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• 作者：Jiao Yang ; Li-Jiao Wang ; Jing-Jing Liu ; Lei Zhong ; Ren-Lin Zheng ; Yong Xu ; Pan Ji ; Chun-Hui Zhang ; Wen-Jing Wang ; Xing-Dong Lin ; Lin-Li Li ; Yu-Quan Wei ; Sheng-Yong Yang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：55
• 期：23
• 页码：10685-10699
• 全文大小：571K
• 年卷期：v.55,no.23(December 13, 2012)
• ISSN：1520-4804

文摘

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鈥揳ctivity 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.