Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth
Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth
复制标题
DOI：
10.1126/sciadv.aau9060
复制
发表时间：
2019-01-01
期刊：
影响因子：
13.6
通讯作者：
Hirota, Tsuyoshi
中科院分区：
文献类型：
--
作者：
Oshima, Tsuyoshi;Niwa, Yoshimi;Hirota, Tsuyoshi
靶向生物钟的化合物已被确定为与生物钟相关的疾病（包括癌症）的潜在治疗方法。我们基于细胞的表型筛选揭示了未表征的时钟调节化合物。通过基于亲和力的靶点去卷积，我们确定了GO289，它强烈延长了昼夜节律周期，作为一种有效的选择性CK 2抑制剂。磷酸蛋白质组学鉴定了时钟蛋白（包括PER 2 S693）上受GO 289抑制的多个磷酸化位点。此外，GO289表现出与细胞时钟功能相关的癌细胞生长的细胞类型依赖性抑制。CK 2 α-GO289复合物的X射线晶体结构揭示了GO289和CK 2特异性残基之间的关键相互作用，并且GO289与激酶之间高度保守的铰链区没有直接相互作用。GO289的发现提供了生物钟和癌症调节之间的直接联系，并揭示了激酶选择性背后的独特设计原理。
Compounds targeting the circadian clock have been identified as potential treatments for clock-related diseases, including cancer. Our cell-based phenotypic screen revealed uncharacterized clock-modulating compounds. Through affinity-based target deconvolution, we identified GO289, which strongly lengthened circadian period, as a potent and selective inhibitor of CK2. Phosphoproteomics identified multiple phosphorylation sites inhibited by GO289 on clock proteins, including PER2 S693. Furthermore, GO289 exhibited cell type-dependent inhibition of cancer cell growth that correlated with cellular clock function. The x-ray crystal structure of the CK2 alpha-GO289 complex revealed critical interactions between GO289 and CK2-specific residues and no direct interaction of GO289 with the hinge region that is highly conserved among kinases. The discovery of GO289 provides a direct link between the circadian clock and cancer regulation and reveals unique design principles underlying kinase selectivity.