Research Institute, National Cancer Center, Goyang 10408, Gyeonggi, Korea.
Int J Mol Sci. 2021 Aug 6;22(16):8488. doi: 10.3390/ijms22168488.
Given the functional attributes of Doublecortin-like kinase 1 (DCLK1) in tumor growth, invasion, metastasis, cell motility, and tumor stemness, it is emerging as a therapeutic target in gastrointestinal cancers. Although a series of specific or nonspecific ATP-competitive inhibitors were identified against DCLK1, different types of scaffolds that can be utilized for the development of highly selective inhibitors or structural understanding of binding specificities of the compounds remain limited. Here, we present our work to repurpose a Janus kinase 1 inhibitor, ruxolitinib as a DCLK1 inhibitor, showing micromolar binding affinity and inhibitory activity. Furthermore, to gain an insight into its interaction mode with DCLK1, a crystal structure of the ruxolitinib-complexed DCLK1 has been determined and analyzed. Ruxolitinib as a nonspecific DCLK1 inhibitor characterized in this work is anticipated to provide a starting point for the structure-guided discovery of selective DCLK1 inhibitors.
鉴于双皮质醇激酶 1（DCLK1）在肿瘤生长、侵袭、转移、细胞迁移和肿瘤干性中的功能属性，它正在成为胃肠道癌症的治疗靶点。尽管已经针对 DCLK1 鉴定出了一系列特异性或非特异性的 ATP 竞争性抑制剂，但可用于开发高选择性抑制剂或化合物结合特异性结构理解的不同类型支架仍然有限。在这里，我们展示了将 Janus 激酶 1 抑制剂鲁索替尼重新用作 DCLK1 抑制剂的工作，显示出微摩尔结合亲和力和抑制活性。此外，为了深入了解其与 DCLK1 的相互作用模式，已经确定并分析了鲁索替尼复合物 DCLK1 的晶体结构。本工作中表征的鲁索替尼作为非特异性 DCLK1 抑制剂，预计将为基于结构的选择性 DCLK1 抑制剂的发现提供起点。
