Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, 12055, Egypt; University of Science & Technology (UST), Daejeon, Yuseong-gu, 34113, Republic of Korea; Center of Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea.
Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre NRC (ID: 60014618), Dokki, Giza, 12622, Egypt.
Eur J Med Chem. 2023 Dec 5;261:115779. doi: 10.1016/j.ejmech.2023.115779. Epub 2023 Sep 15.
A series of 36 pyrazol-4-yl pyridine derivatives (8a-i, 9a-i, 10a-i, and 11a-i) was designed, synthesized, and evaluated for its antiproliferative activity over NCI-60 cancer cell line panel and inhibitory effect against JNK isoforms (JNK1, JNK2, and JNK3). All the synthesized compounds were tested against the NCI-60 cancer cell line panel. Compounds 11b, 11c, 11g, and 11i were selected to determine their GI and exerted a superior potency over the reference standard SP600125 against the tested cell lines. 11c showed a GI of 1.28 μM against K562 leukemic cells. Vero cells were used to assess 11c cytotoxicity compared to the tested cancer cells. The target compounds were tested against hJNK isoforms in which compound 11e exhibited the highest potency against JNK isoforms with IC values of 1.81, 12.7, and 10.5 nM against JNK1, JNK2, and JNK3, respectively. Kinase profiling of 11e showed higher JNK selectivity in 50 kinase panels. Compounds 11c and 11e showed cell population arrest at the G2/M phase, induced early apoptosis, and slightly inhibited beclin-1 production at higher concentrations in K562 leukemia cells relative to SP600125. NanoBRET assay of 11e showed intracellular JNK1 inhibition with an IC of 2.81 μM. Also, it inhibited CYP2D6 and 3A4 with different extent and its hERG activity showed little cardiac toxicity with an IC of 4.82 μM. hJNK3 was used as a template to generate the hJNK1 crystal structure to explore the binding mode of 11e (PDB ID: 8ENJ) with a resolution of 2.8 °A and showed a typical type I kinase inhibition against hJNK1. Binding energy scores showed that selectivity of 11e towards JNK1 could be attributed to additional hydrophobic interactions relative to JNK3.
设计、合成了一系列 36 个吡唑-4-基吡啶衍生物（8a-i、9a-i、10a-i 和 11a-i），并对其在 NCI-60 癌细胞系中的抗增殖活性和对 JNK 同工型（JNK1、JNK2 和 JNK3）的抑制作用进行了评价。所有合成的化合物都针对 NCI-60 癌细胞系进行了测试。选择化合物 11b、11c、11g 和 11i 来确定它们的 GI，并对测试的细胞系表现出优于参考标准 SP600125 的活性。11c 对白血病细胞 K562 的 GI 为 1.28 μM。用 Vero 细胞评估 11c 的细胞毒性与测试的癌细胞相比。目标化合物在 hJNK 同工型中进行了测试，其中化合物 11e 对 JNK 同工型的活性最高，对 JNK1、JNK2 和 JNK3 的 IC 值分别为 1.81、12.7 和 10.5 nM。11e 的激酶谱分析显示在 50 个激酶谱中具有更高的 JNK 选择性。与 SP600125 相比，化合物 11c 和 11e 在 K562 白血病细胞中可使细胞群体停滞在 G2/M 期，诱导早期凋亡，并在较高浓度下轻微抑制 beclin-1 的产生。NanoBRET 试验显示 11e 对 JNK1 的抑制作用具有 IC50 为 2.81 μM。此外，它还不同程度地抑制了 CYP2D6 和 3A4，其 hERG 活性的 IC50 为 4.82 μM。使用 hJNK3 作为模板生成 hJNK1 晶体结构，以探索 11e（PDB ID：8ENJ）的结合模式，分辨率为 2.8 °A，并显示出对 hJNK1 的典型 I 型激酶抑制作用。结合能评分表明，与 JNK3 相比，11e 对 JNK1 的选择性可能归因于额外的疏水相互作用。
