Exploration of N-(2-aminoethyl)piperidine-4-carboxamide as a potential scaffold for development of VEGFR-2, ERK-2 and Abl-1 multikinase inhibitor
Exploration of N-(2-aminoethyl)piperidine-4-carboxamide as a potential scaffold for development of VEGFR-2, ERK-2 and Abl-1 multikinase inhibitor
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N-(2-氨基乙基)哌啶-4-甲酰胺作为开发 VEGFR-2、ERK-2 和 Abl-1 多激酶抑制剂的潜在支架的探索
DOI：
10.1016/j.bmc.2013.07.026
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发表时间：
2013-09-15
影响因子：
3.5
通讯作者：
Jiang, Yuyang
中科院分区：
文献类型：
--
作者：
Jin, Feng;Gao, Dan;Jiang, Yuyang
VEGFR、ERK和Abl分别被确定为良好的药物靶点，它们的串扰也得到了很好的阐述。多靶点药物更有利于肿瘤的治疗，但由于这三种蛋白结构的多样性，目前还没有同时作用于这三种蛋白的抑制剂。其中，N-(4-((2-(2-(naphthaen-1-yl)acetamido)ethyl)carbamoyl)piperidin-4-yl)-6-(trifluoromethyl)nicotinamide(Net T，6a)通过支持向量机、相似性搜索和分子对接相结合的方法被发现是一种针对VEGFR-2、ERK-2和Abl-1激酶的活性支架。以方便的方法合成了NPT及其衍生物，并初步评价了其对人肝癌细胞株HepG2的体外抗增殖作用。具有代表性的化合物6b的IC50值为11.3mU M，并能显著诱导HepG2细胞的凋亡。此外，这些化合物对1(562)细胞具有较好的抗增殖活性，例如化合物6b的IC50值为4.5 mU M。根据ABL抑制剂的肝毒性案例报道，研究了合成化合物对正常肝细胞株(QSG7701和HL7702)的细胞毒性，6b具有与阳性对照伊马替尼相似的毒性作用，大多数化合物在100 mU M下显示出低于35%的抑制活性。分子对接研究表明，6b分别与VEGFR-2、ERK-2和Abl-1激酶相互作用。我们的数据提示，6b的生物活性可能来源于VEGFR-2、ERK-2和Abl-1抑制的协同作用。(C)2013爱思唯尔有限公司。保留所有权利。
VEGFR, ERK and Abl had been respectively identified as good drug targets, and their crosstalk also had been well elaborated. Multitarget drugs were more advantageous for cancer treatment, however, no inhibitors simultaneously acting on the three proteins were developed due to their structural diversities. Herein, N-(4-((2-(2-(naphthaen-1-yl)acetamido)ethyl)carbamoyl)piperidin-4-yl)-6-(trifluoromethyl)nicotinamide (NEPT, 6a) was discovered as an active scaffold against VEGFR-2, ERK-2 and Abl-1 kinases through the combination of support vector machine, similarity searching and molecular docking. NEPT and its derivatives were synthesized by convenient routine, their in vitro anti-proliferative abilities against human liver cancer cell line HepG2 were preliminarily evaluated. A representative compound 6b showed an IC50 value of 11.3 mu M and induced significant HepG2 cells apoptosis. Besides, these compounds displayed better anti-proliferative abilities against 1(562 cells (a cell line with typical hyperactivity of the above multikinases), for example compound 6b exhibited an IC50 value of 4.5 mu M. Based on hepatotoxicity case reports of Abl inhibitors, cytotoxicity of synthetic compounds against normal liver cell lines (QSG7701 and HL7702) was studied, 6b had a similar toxic effect with positive control imatinib, and most compounds showed less than 35% inhibition activities at 100 mu M. Molecular docking study disclosed interactions of 6b with VEGFR-2, ERK-2 and Abl-1 kinases, respectively. Our data suggested the biological activities of 6b may derived from collaborative effects of VEGFR-2, ERK-2 and Abl-1 inhibition. (C) 2013 Elsevier Ltd. All rights reserved.