Inhibitors of the RET tyrosine kinase based on a 2-(alkylsulfanyl)-4-(3-thienyl) nicotinonitrile scaffold
Inhibitors of the RET tyrosine kinase based on a 2-(alkylsulfanyl)-4-(3-thienyl) nicotinonitrile scaffold
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DOI：
10.1016/j.ejmech.2010.03.017
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发表时间：
2010-07-01
影响因子：
6.7
通讯作者：
Kunick, Conrad
中科院分区：
文献类型：
--
作者：
Brandt, Wiebke;Mologni, Luca;Kunick, Conrad
在优化2-（4-氟苄基硫烷基）-4-（2-噻吩基）-5，6，7，8-四氢喹啉-3-腈（1a）（一种源自筛选活动的癌症相关酪氨酸激酶RET的弱抑制剂）的方法中，制备了具有3-噻吩基取代的类似物。在这些新的衍生物中，2-氨基-6-{[2-（4-氯苯基）-2-氧代乙基]硫基}-4-（3-噻吩基）吡啶-3，5-二甲腈（13 g）被鉴定为亚微摩尔RET抑制剂，对ALK和ABL激酶分别显示出3倍和100倍的选择性。该新型抑制剂在微摩尔浓度范围内对RET依赖性和RET非依赖性癌细胞系均表现出抗增殖活性。对接实验表明，在目标激酶的ATP结合口袋中的新的抑制剂的结合模式，解释所观察到的结构活性关系。(c)2010年Elsevier Masson SAS。All rights reserved.
In an approach to optimize 2-(4-fluorobenzylsulfanyl)-4-(2-thienyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (1a), a weak inhibitor of the cancer-related tyrosine kinase RET originating from a screening campaign, analogues with 3-thienyl substitution were prepared. Among the novel derivatives, 2-amino-6-{[2-(4-chlorophenyl)-2-oxoethyl]sulfanyl}-4-(3-thienyl)pyridine-3,5-dicarbonitrile (13g) was identified as a submicromolar RET inhibitor, displaying 3- and 100-fold selectivity versus ALK and ABL kinases, respectively. The novel inhibitor exhibited antiproliferative activity in the micromolar concentration range against both RET-dependent and RET-independent cancer cell lines. Docking experiments suggest a binding mode of the new inhibitors in the ATP binding pocket of the target kinase, explaining the observed structure activity relationships. (c) 2010 Elsevier Masson SAS. All rights reserved.