Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO 80045, USA.
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO 80045, USA.
Bioorg Med Chem. 2020 Mar 1;28(5):115303. doi: 10.1016/j.bmc.2019.115303. Epub 2020 Jan 12.
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.
p90 核糖体 S6 激酶 2（RSK2）的活性已成为癌症治疗的一个有吸引力的靶点，因为它在调节多种细胞过程中发挥作用，如细胞转化和增殖。已经确定了几种泛 RSK 抑制剂，其中 BI-D1870 和伪类似物 LJH685 和 LJI308 是最具选择性、最有效和最常使用的小分子抑制剂。我们设计并合成了一系列蝶啶酮和嘧啶，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结合，并测量了它们对 MOLM-13 急性髓系白血病（AML）细胞系中细胞活力和细胞毒性的影响。我们研究的结果支持在 MOLM-13 细胞中可以实现 RSK2 抑制而不会产生强烈的细胞毒性。本研究的结构活性数据将作为开发新型 RSK2 抑制剂的平台。
