Abstract

The STE20 kinase family is a complex signalling cascade that regulates cytoskeletal organisation and modulates the stress response. This signalling cascade includes various kinase mediators, such as TAOK1 and MAP4K5. The dysregulation of the STE20 kinase pathway is linked with cancer malignancy. A small-molecule inhibitor targeting the STE20 kinase pathway has therapeutic potential. In this study, a structure-based virtual screening (SBVS) approach was used to identify potential dual TAOK1 and MAP4K5 inhibitors. Enzymatic assays confirmed three potential dual inhibitors (>50% inhibition) from our virtual screening, and analysis of the TAOK1 and MAP4K5 binding sites indicated common interactions for dual inhibition. Compound 1 revealed potent inhibition of colorectal and lung cancer cell lines. Furthermore, compound 1 arrested cancer cells in the G0/G1 phase, which suggests the induction of apoptosis. Altogether, we show that the STE20 signalling mediators TAOK1 and MAP4K5 are promising targets for drug research.

摘要

STE20 激酶家族是一个复杂的信号级联，可调节细胞骨架组织并调节应激反应。该信号级联包括各种激酶介质，例如 TAOK1 和 MAP4K5。STE20 激酶通路的失调与癌症恶性肿瘤有关。一种针对 STE20 激酶通路的小分子抑制剂具有治疗潜力。在本研究中，采用基于结构的虚拟筛选 (SBVS) 方法来鉴定潜在的 TAOK1 和 MAP4K5 双重抑制剂。酶测定从我们的虚拟筛选中证实了三种潜在的双重抑制剂（>50% 抑制），并且 TAOK1 和 MAP4K5 结合位点的分析表明了双重抑制的常见相互作用。化合物 1 显示出对结直肠癌细胞系和肺癌细胞系的有效抑制作用。此外，化合物 1 将癌细胞阻滞在 G0/G1 期，这表明可以诱导细胞凋亡。总而言之，我们表明 STE20 信号传导介质 TAOK1 和 MAP4K5 是药物研究的有希望的靶点。