G-四链体(G4)序列,可以折叠成更高阶的G4结构,在人类基因组中丰富,并且在参与人类癌症发生的许多基因的启动子区域中过度存在,programming,和转移。它们是G4结合小分子的合理靶标,这将,在启动子G4s的情况下,导致这些基因的转录下调。然而,目前,只有极少数的G4s及其配体复合物具有结构信息。这种限制,再加上目前有关大多数复杂人类癌症的含G4基因的有限信息,已经导致了表型主导的G4配体药物发现方法的发展。这种方法通过发现几代三-和四-取代的萘二酰亚胺(ND)配体来说明,发现这些配体在胰腺癌细胞系中显示出有效的生长抑制,并且在这种难以治疗的疾病的体内模型中具有活性。发现的循环最终产生了高效的四取代ND衍生物,QN-302,目前正在1期临床试验中进行评估。本文呈现了表达已被QN-302下调的主要基因:所有基因都含有G4倾向并且已发现在人胰腺癌中上调。其中一些基因在其他人类癌症中也被上调,支持以下假设:QN-302是一种超越胰腺癌的潜在效用的泛G4药物.
G-quadruplex (G4) sequences, which can fold into higher-order G4 structures, are abundant in the human genome and are over-represented in the promoter regions of many genes involved in human cancer initiation, progression, and metastasis. They are plausible targets for G4-binding small molecules, which would, in the case of promoter G4s, result in the transcriptional downregulation of these genes. However, structural information is currently available on only a very small number of G4s and their ligand complexes. This limitation, coupled with the currently restricted information on the G4-containing genes involved in most complex human cancers, has led to the development of a phenotypic-led approach to G4 ligand drug discovery. This approach was illustrated by the discovery of several generations of tri- and tetra-substituted naphthalene diimide (ND) ligands that were found to show potent growth inhibition in pancreatic cancer cell lines and are active in in vivo models for this hard-to-treat disease. The cycles of discovery have culminated in a highly potent tetra-substituted ND derivative, QN-302, which is currently being evaluated in a Phase 1 clinical trial. The major genes whose expression has been down-regulated by QN-302 are presented here: all contain G4 propensity and have been found to be up-regulated in human pancreatic cancer. Some of these genes are also upregulated in other human cancers, supporting the hypothesis that QN-302 is a pan-G4 drug of potential utility beyond pancreatic cancer.