Department of Medicinal Chemistry, School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
Department of Radiation Oncology, Tianjin Union Medical Center, Tianjin, 300121, China.
Eur J Med Chem. 2019 Nov 1;181:111535. doi: 10.1016/j.ejmech.2019.07.038. Epub 2019 Jul 25.
A series of novel, highly potent, selective CDK9 inhibitors with cancer stem cells (CSCs) inhibition activity were designed and synthesized for non-small-cell lung cancer (NSCLC) therapy. Structure-activity relationship analysis based on enzymatic and cellular activities led to the discovery of a promising inhibitor 21e. 21e potently inhibited CDK9 with IC value of 11 nM and suppressed the stemness properties of NSCLC effectively. It could decrease the stemness phenotypes of NSCLC cells, including tumor sphere formation, side-population and stemness markers abundance. 21e displayed good selectivity over the CDK family kinases and kinase profiling assay against 381 kinases. In addition, 21e inhibited cell proliferation, colony-formation, and cell cycle progression and induced apoptosis in NSCLC. In H1299 xenograft mouse model, a once-daily dose of compound 21e at 20 mg/kg significantly suppressed the tumor growth without obvious toxicity. Studies of mechanisms of action indicated that 21e efficiently inhibited CDK9 signaling pathway and stemness both in vitro and in vivo. Collectively, 21e as a novel CDK9 inhibitor with CSCs inhibition properties could be a promising agent for the treatment of NSCLC.
一系列新型、高效、选择性的细胞周期蛋白依赖性激酶 9（CDK9）抑制剂具有抑制癌症干细胞（CSCs）的活性，被设计并合成用于治疗非小细胞肺癌（NSCLC）。基于酶和细胞活性的构效关系分析，发现了一种有前途的抑制剂 21e。21e 能有效抑制 CDK9，IC 值为 11nM，并能有效抑制 NSCLC 的干性。它可以降低 NSCLC 细胞的干性表型，包括肿瘤球形成、侧群和干性标志物丰度。21e 在 CDK 家族激酶中具有良好的选择性，对 381 种激酶的激酶谱分析也显示出良好的选择性。此外，21e 能抑制 NSCLC 细胞的增殖、集落形成、细胞周期进程，并诱导细胞凋亡。在 H1299 荷瘤小鼠模型中，化合物 21e 每天一次以 20mg/kg 的剂量给药能显著抑制肿瘤生长，而无明显毒性。作用机制的研究表明，21e 能有效抑制 CDK9 信号通路和体内外的干性。总的来说，21e 作为一种具有 CSCs 抑制特性的新型 CDK9 抑制剂，可能是治疗 NSCLC 的一种有前途的药物。
