Abstract:
Transcription factor NF-κB potently activates anti-apoptotic genes, and its inactivation significantly reduces tumor cell survival following genotoxic stresses. We identified two structurally distinct lead compounds that selectively inhibit NF-κB activation by DNA double-strand breaks, but not by other stimuli, such as TNFα. Our compounds do not directly inhibit previously identified regulators of this pathway, most critically including IκB kinase (IKK), but inhibit signal transmission in-between ATM, PARP1, and IKKγ. Deconvolution strategies, including derivatization and in vitro testing in multi-kinase panels, yielded shared targets, cdc-like kinase (CLK) 2 and 4, as essential regulators of DNA damage-induced IKK and NF-κB activity. Both leads sensitize to DNA damaging agents by increasing p53-induced apoptosis, thereby reducing cancer cell viability. We propose that our lead compounds and derivatives can be used in context of genotoxic therapy-induced or ongoing DNA damage to increase tumor cell apoptosis, which may be beneficial in cancer treatment.
摘要:
转录因子NF-κB有效激活抗凋亡基因,其失活显著降低基因毒性应激后的肿瘤细胞存活率。我们确定了两种结构不同的先导化合物,它们通过DNA双链断裂选择性地抑制NF-κB激活,但不是通过其他刺激,如TNFα。我们的化合物不会直接抑制先前确定的该途径的调节剂,最关键的包括IκB激酶(IKK),但是抑制了ATM之间的信号传输,PARP1和IKKγ。反卷积策略,包括衍生化和多激酶面板的体外测试,产生了共享目标,cdc样激酶(CLK)2和4,是DNA损伤诱导的IKK和NF-κB活性的重要调节因子。两种引线都通过增加p53诱导的细胞凋亡而对DNA损伤剂敏感,从而降低癌细胞活力。我们建议我们的先导化合物和衍生物可用于基因毒性治疗诱导或持续DNA损伤的背景下,以增加肿瘤细胞凋亡。这可能对癌症治疗有益。