Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy.
Department of Pharmacy and Biotechnology, Alma Mater Studiorum─University of Bologna, 40126 Bologna, Italy.
J Med Chem. 2022 Sep 22;65(18):12055-12067. doi: 10.1021/acs.jmedchem.2c00772. Epub 2022 Sep 8.
G-quadruplex (G4) ligands are investigated to discover new anticancer drugs with increased cell-killing potency. These ligands can induce genome instability and activate innate immune genes at non-cytotoxic doses, opening the discovery of cytostatic immune-stimulating ligands. However, the interplay of G4 affinity/selectivity with cytotoxicity and immune gene activation is not well-understood. We investigated a series of closely related hydrazone derivatives to define the molecular bases of immune-stimulation activity. Although they are closely related to each other, such derivatives differ in G4 affinity, cytotoxicity, genome instability, and immune gene activation. Our findings show that G4 affinity of ligands is a critical feature for immune gene activation, whereas a high cytotoxic potency interferes with it. The balance of G4 stabilization cytotoxicity can determine the level of immune gene activation in cancer cells. Thus, we propose a new rationale based on low cell-killing potency and high immune stimulation to discover effective anticancer G4 ligands.
G-四链体 (G4) 配体被研究用于发现具有更高细胞杀伤效力的新型抗癌药物。这些配体可以在非细胞毒性剂量下诱导基因组不稳定性并激活先天免疫基因，从而发现具有细胞抑制作用的免疫刺激配体。然而，G4 亲和力/选择性与细胞毒性和免疫基因激活之间的相互作用尚未得到很好的理解。我们研究了一系列密切相关的腙衍生物，以确定免疫刺激活性的分子基础。尽管它们彼此密切相关，但这些衍生物在 G4 亲和力、细胞毒性、基因组不稳定性和免疫基因激活方面存在差异。我们的研究结果表明，配体的 G4 亲和力是免疫基因激活的关键特征，而高细胞毒性则会干扰其激活。G4 稳定化与细胞毒性之间的平衡可以决定癌细胞中免疫基因激活的水平。因此，我们提出了一种基于低细胞杀伤效力和高免疫刺激的新原理，用于发现有效的抗癌 G4 配体。
