Structure-activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor
Structure-activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor
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DOI：
10.1016/j.ejmech.2014.01.042
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发表时间：
2014-03-21
影响因子：
6.7
通讯作者：
Hoff, Bard Helge
中科院分区：
文献类型：
--
作者：
Bugge, Steffen;Kaspersen, Svein Jacob;Hoff, Bard Helge
基于硫代[2，3-d]嘧啶骨架，合成了一系列新的4-氨基-6-芳基硫代嘧啶类化合物，并对其作为EGFR酪氨酸激酶抑制剂进行了评价。体外活性强烈依赖于6-芳环上的取代方式、立体化学和次级4-氨基上的碱性。通过结合活性片段进行逐步优化，发现了具有EGFR IC50<；1 nm的三个结构。最有效的候选药物对EGFR及其突变体L858R和L861Q的IC50为0.3 nM。使用人类癌细胞株和EGFR-L858R报告细胞系统的研究显示了良好的细胞潜力，验证了所识别的硫代嘧啶类化合物是有希望的先导结构。(C)2014年爱思唯尔·马森公司。版权所有。
Based on the thieno[2,3-d]pyrimidine scaffold, a series of new 4-amino-6-aryl thienopyrimidines have been prepared and evaluated as EGFR tyrosine kinase inhibitors. The in vitro activity was found to depend strongly on the substitution pattern in the 6-aryl ring, the stereochemistry, and the basicity at the secondary 4-amino group. A stepwise optimization by combination of active fragments led to the discovery of three structures with EGFR IC50 < 1 nM. The most potent drug candidate had an IC50 of 0.3 nM towards EGFR and its mutants L858R and L861Q. Studies using human cancer cell lines and an EGFR-L858R reporter cell system revealed good cellular potency, verifying the identified thienopyrimidines as promising lead structures. (C) 2014 Elsevier Masson SAS. All rights reserved.