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Substituted pteridinones as p90 ribosomal S6 protein kinase (RSK) inhibitors: A structure-activity study.
Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2020-01-12 , DOI: 10.1016/j.bmc.2019.115303
Kimberly A Casalvieri 1 , Christopher J Matheson 1 , Donald S Backos 1 , Philip Reigan 1
Affiliation  

The activity of p90 ribosomal S6 kinase 2 (RSK2) has emerged as an attractive target for cancer therapy due to its role in the regulation of diverse cellular processes, such as cell transformation and proliferation. Several pan-RSK inhibitors have been identified with BI-D1870 and the pseudo-analogs LJH685 and LJI308 being the most selective, potent, and frequently used small molecule inhibitors. We designed and synthesized a series of pteridinones and pyrimidines to evaluate the structural features of BI-D1870 that are required for RSK2 inhibition. We have identified inhibitors of RSK2 activity, evaluated their target engagement in cells, and measured their effect on cell viability and cytotoxicity in the MOLM-13 acute myeloid leukemia (AML) cell line. The results of our studies support that RSK2 inhibition can be achieved in MOLM-13 cells without potent cytotoxicity. The structure-activity data from this study will be used as a platform to develop novel RSK2 inhibitors.

中文翻译:

取代的翼龙类作为p90核糖体S6蛋白激酶(RSK)抑制剂:一项结构活性研究。

p90核糖体S6激酶2(RSK2)的活性已成为癌症治疗的引人注目的靶标,因为它在多种细胞过程(如细胞转化和增殖)的调节中起着重要作用。几种泛RSK抑制剂已被BI-D1870鉴定,假类似物LJH685和LJI308是最具选择性,最有效和最常用的小分子抑制剂。我们设计和合成了一系列的翼龙和嘧啶,以评估BI-D1870抑制RSK2所需的结构特征。我们已经确定了RSK2活性的抑制剂,评估了它们在细胞中的靶标参与度,并测量了它们对MOLM-13急性骨髓性白血病(AML)细胞系中细胞活力和细胞毒性的影响。我们的研究结果支持在MOLM-13细胞中实现RSK2抑制而没有有效的细胞毒性。这项研究的结构活性数据将用作开发新型RSK2抑制剂的平台。
更新日期:2020-01-13
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