Abnous Khalil, Manavi Hesam, Mehri Soghra, Alibolandi Mona, Kamali Hossein, Ghandadi Morteza, Hadizadeh Farzin
Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, I.R. Iran.
Student Research Committee, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, I.R. Iran.
Res Pharm Sci. 2017 Jun;12(3):196-203. doi: 10.4103/1735-5362.207200.
PIM-1 protein kinase inhibitor belongs to a novel class of serine/threonine kinases. As PIM-1 is overexpressed in cancer cells and possesses oncogenic functions, its inhibition provides a new option in cancer therapy. In this study, inhibitory effects of seven analogues of 1, 2-dihydropyridine-3-carbonitrile derivatives , on the activity of recombinant PIM-1 were evaluated using dimethylthiazol diphenyltetrazolium bromide (MTT) assay. The PIM-1 protein kinase inhibitory potencies and the cytotoxicity effects of tested compounds were respectively as follows: > > > > > > and > > > > > > , respectively. The compound with methylthio imidazole substituent at C-3 position and benzodioxole substituent at C-6 position of 2-imino-1, 2-dihydropyridine-3- carbonitrile structure showed the strongest PIM-1 inhibitory effect (IC = 111.01 nM), while the compound with methythio imidazole substituent at C-3 position and benzodioxole substituent at C-6 position of 2-oxo-1, 2-dihydropyridine-3- carbonitrile structure exhibited the least inhibition activity (IC = 433.71 nM). The docking results showed that all tested compounds localized appropriately in the middle of binding cavity after docking procedure, demonstrating suitable interactions between ligands and protein. This study demonstrated that the PIM-1 inhibitory potencies of newly synthesized compounds were in submicromolar concentrations (IC < 150 nM) while they exhibited low cytotoxicity on HT-29 cell line (IC> 130 μM). Altogether, our data indicated that compounds , , could be considered as new potent non-toxic PIM-1 inhibitors which could be used in combination with routine anti-proliferative drugs.
PIM-1蛋白激酶抑制剂属于一类新型的丝氨酸/苏氨酸激酶。由于PIM-1在癌细胞中过度表达并具有致癌功能，对其进行抑制为癌症治疗提供了新的选择。在本研究中，使用甲基噻唑基二苯基四氮唑溴盐（MTT）法评估了1,2-二氢吡啶-3-腈衍生物的七种类似物对重组PIM-1活性的抑制作用。测试化合物的PIM-1蛋白激酶抑制效力和细胞毒性作用分别如下：> > > > > > 和 > > > > > > > > 。在2-亚氨基-1,2-二氢吡啶-3-腈结构的C-3位带有甲硫基咪唑取代基且在C-6位带有苯并二恶唑取代基的化合物显示出最强的PIM-1抑制作用（IC = 111.01 nM），而在2-氧代-1,2-二氢吡啶-3-腈结构的C-3位带有甲硫基咪唑取代基且在C-6位带有苯并二恶唑取代基的化合物表现出最小的抑制活性（IC = 433.71 nM）。对接结果表明，所有测试化合物在对接程序后均适当地定位在结合腔的中部，表明配体与蛋白质之间存在合适的相互作用。本研究表明，新合成化合物的PIM-1抑制效力处于亚微摩尔浓度（IC < 150 nM），而它们对HT-29细胞系表现出低细胞毒性（IC> 130 μM）。总之，我们的数据表明化合物 、 、 可被视为新型强效无毒PIM-1抑制剂，可与常规抗增殖药物联合使用。
