Laboratory of Signal Transduction in Tumor Cells, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
Laboratory of Medicinal Chemistry, Leibniz Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany.
Cell Chem Biol. 2023 Oct 19;30(10):1303-1312.e3. doi: 10.1016/j.chembiol.2023.06.027. Epub 2023 Jul 27.
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.
转录因子 NF-κB 能强力激活抗凋亡基因，其失活能显著降低肿瘤细胞在遭受遗传毒性应激后的存活能力。我们鉴定出两种结构上截然不同的先导化合物，它们能选择性地抑制由 DNA 双链断裂引发的 NF-κB 激活，而不抑制其他刺激物（如 TNFα）引发的激活。我们的化合物并不直接抑制该通路中先前已鉴定的调控因子，特别是包括 IκB 激酶（IKK），而是抑制 ATM、PARP1 和 IKKγ 之间的信号传递。去卷积策略，包括衍生化和在多激酶面板中的体外测试，产生了共同的靶标，CDC 样激酶（CLK）2 和 4，它们是 DNA 损伤诱导的 IKK 和 NF-κB 活性的必需调控因子。这两种先导化合物通过增加 p53 诱导的细胞凋亡来增敏 DNA 损伤剂，从而降低癌细胞的活力。我们提出，我们的先导化合物及其衍生物可用于遗传毒性治疗诱导或正在进行的 DNA 损伤，以增加肿瘤细胞凋亡，这可能对癌症治疗有益。
