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 μM and induced significant HepG2 cells apoptosis. Besides, these compounds displayed better anti-proliferative abilities against K562 cells (a cell line with typical hyperactivity of the above multikinases), for example compound 6b exhibited an IC₅₀ value of 4.5 μM. 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 μM. 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.

VEGFR，ERK和Abl分别被确定为良好的药物靶标，并且它们的串扰也得到了很好的阐述。多靶点药物对癌症的治疗更为有利，但是，由于它们的结构多样性，没有开发出同时作用于这三种蛋白质的抑制剂。在本文中，发现N-（4-（（2-（2-（萘甲-1-基）乙酰氨基）乙基）氨基甲酰基）哌啶-4-基）-6-（三氟甲基）烟酰胺（NEPT，6a）通过支持向量机，相似性搜索和分子对接的组合来抵抗VEGFR-2，ERK-2和Abl-1激酶。NEPT及其衍生物是通过方便的常规方法在体外合成的初步评估了其对人肝癌细胞系HepG2的抗增殖能力。代表性化合物6b的IC ₅₀值为11.3μM，并诱导了显着的HepG2细胞凋亡。此外，这些化合物对K562细胞（具有上述多激酶典型的过度活跃的细胞系）显示出更好的抗增殖能力，例如化合物6b的IC ₅₀值为4.5μM。根据Abl抑制剂的肝毒性病例报告，研究了合成化合物对正常肝细胞系（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100μM时显示不到35％的抑制活性。分子对接研究揭示了6b分别与VEGFR-2，ERK-2和Abl-1激酶的相互作用。我们的数据表明6b的生物学活性可能源于VEGFR-2，ERK-2和Abl-1抑制的协同作用。