Zhou Qingqing, Phoa Athena F, Abbassi Ramzi H, Hoque Monira, Reekie Tristan A, Font Josep S, Ryan Renae M, Stringer Brett W, Day Bryan W, Johns Terrance G, Munoz Lenka, Kassiou Michael
QIMR Berghofer Medical Research Institute , 300 Herston Road, Herston, Queensland 4006, Australia.
Oncogenic Signaling Laboratory, Centre for Cancer Research, Hudson Institute of Medical Research , 27 Wright Street, Clayton, Victoria 3168, Australia.
J Med Chem. 2017 Mar 9;60(5):2052-2070. doi: 10.1021/acs.jmedchem.6b01840. Epub 2017 Feb 28.
The DYRK family contains kinases that are up-regulated in malignancy and control several cancer hallmarks. To assess the anticancer potential of inhibitors targeting DYRK kinases, we developed a series of novel DYRK inhibitors based on the 7-azaindole scaffold. All compounds were tested for their ability to inhibit DYRK1A, DYRK1B, DYRK2, and the structurally related CLK1. The library was screened for anticancer efficacy in established and stem cell-like glioblastoma cell lines. The most potent inhibitors (IC ≤ 50 nM) significantly decreased viability, clonogenic survival, migration, and invasion of glioblastoma cells. Target engagement was confirmed with genetic knockdown and the cellular thermal shift assay. We demonstrate that DYRK1A's thermal stability in cells is increased upon compound treatment, confirming binding in cells. In summary, we present synthesis, structure-activity relationship, and efficacy in glioblastoma-relevant models for a library of novel 7-azaindoles.
DYRK家族包含在恶性肿瘤中上调并控制多种癌症特征的激酶。为了评估靶向DYRK激酶的抑制剂的抗癌潜力，我们基于7-氮杂吲哚支架开发了一系列新型DYRK抑制剂。测试了所有化合物抑制DYRK1A、DYRK1B、DYRK2以及结构相关的CLK1的能力。在已建立的和干细胞样胶质母细胞瘤细胞系中筛选该文库的抗癌功效。最有效的抑制剂（IC≤50 nM）显著降低了胶质母细胞瘤细胞的活力、克隆形成存活率、迁移和侵袭能力。通过基因敲低和细胞热位移分析证实了靶点结合。我们证明，化合物处理后细胞中DYRK1A的热稳定性增加，证实了其在细胞中的结合。总之，我们展示了一个新型7-氮杂吲哚文库在胶质母细胞瘤相关模型中的合成、构效关系和功效。
