AIM This study aimed at screening and development of Pim-1 inhibitors as anticancer agent. BACKGROUND Pim-1, a member of the Ser/Thr kinase family, plays a crucial role in cell proliferation and is being regarded as a promising target for cancer therapeutics. OBJECTIVE The present work focused on screening more potent Pim-1 inhibitors by in-silico method and biological evaluation. MATERIALS AND METHODS To identify more potent Pim-1 inhibitors, a GALAHAD pharmacophore model was constructed based on nine known Pim-1 inhibitors and followed by in silico screening including pharmacophore and molecular docking-based virtual screening. The hit compounds were further assessed the Pim-1, 2, and 3 kinase activities and the anticancer inhibition property against human myeloma RPMI-8226 and U266 cells using cytotoxicity studies. RESULTS Based on Qfit value (from pharmacophore), docking score and clustering analysis, six compounds including C445_0268, C470_0769, 4456_0744, 0806_0325, G395_1510 and V023_3227 were hit. Binding mode analysis showed that hydrogen bond, hydrophobic and π-π stacking interactions dominated the bindings of these compounds to Pim-1. The further biological evaluation indicated that compounds C445_0268 and C470_0769 possessed excellent pan-Pim kinase activities and inhibited the growths of RPMI-8226 and U266 cell lines with IC50 values lower than 3.75 μM. CONCLUSION We reported a series of Pim-1 small molecule inhibitors that could serve as the lead compounds to develop new targeted anticancer therapeutics.

中文翻译：

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通过药效团模型、基于分子对接的虚拟筛选和生物学评价鉴定 Pim-1 激酶抑制剂。

目的本研究旨在筛选和开发作为抗癌剂的Pim-1抑制剂。背景 Pim-1 是 Ser/Thr 激酶家族的成员，在细胞增殖中起关键作用，被认为是癌症治疗的有希望的靶点。目的目前的工作重点是通过计算机方法和生物学评价筛选更有效的 Pim-1 抑制剂。材料和方法 为了鉴定更有效的 Pim-1 抑制剂，基于九种已知 Pim-1 抑制剂构建 GALAHAD 药效团模型，然后进行计算机筛选，包括药效团和基于分子对接的虚拟筛选。使用细胞毒性研究进一步评估了命中化合物的 Pim-1、2 和 3 激酶活性以及对人骨髓瘤 RPMI-8226 和 U266 细胞的抗癌抑制特性。结果 根据 Qfit 值（来自药效团）、对接分数和聚类分析，命中了包括 C445_0268、C470_0769、4456_0744、0806_0325、G395_1510 和 V023_3227 在内的六种化合物。结合模式分析表明，氢键、疏水性和 π-π 堆积相互作用主导了这些化合物与 Pim-1 的结合。进一步的生物学评价表明，化合物C445_0268和C470_0769具有优异的泛Pim激酶活性，抑制RPMI-8226和U266细胞系的生长，IC50值低于3.75 μM。结论 我们报道了一系列 Pim-1 小分子抑制剂，可作为开发新靶向抗癌治疗药物的先导化合物。G395_1510 和 V023_3227 被击中。结合模式分析表明，氢键、疏水性和 π-π 堆积相互作用主导了这些化合物与 Pim-1 的结合。进一步的生物学评价表明，化合物C445_0268和C470_0769具有优异的泛Pim激酶活性，抑制RPMI-8226和U266细胞系的生长，IC50值低于3.75 μM。结论 我们报道了一系列 Pim-1 小分子抑制剂，可作为开发新靶向抗癌治疗药物的先导化合物。G395_1510 和 V023_3227 被击中。结合模式分析表明，氢键、疏水性和 π-π 堆积相互作用主导了这些化合物与 Pim-1 的结合。进一步的生物学评价表明，化合物C445_0268和C470_0769具有优异的泛Pim激酶活性，抑制RPMI-8226和U266细胞系的生长，IC50值低于3.75 μM。结论 我们报道了一系列 Pim-1 小分子抑制剂，可作为开发新靶向抗癌治疗药物的先导化合物。进一步的生物学评价表明，化合物C445_0268和C470_0769具有优异的泛Pim激酶活性，抑制RPMI-8226和U266细胞系的生长，IC50值低于3.75 μM。结论 我们报道了一系列 Pim-1 小分子抑制剂，可作为开发新靶向抗癌治疗药物的先导化合物。进一步的生物学评价表明，化合物C445_0268和C470_0769具有优异的泛Pim激酶活性，抑制RPMI-8226和U266细胞系的生长，IC50值低于3.75 μM。结论 我们报道了一系列 Pim-1 小分子抑制剂，可作为开发新靶向抗癌治疗药物的先导化合物。