The Potent G-Quadruplex-Binding Compound QN-302 Downregulates S100P Gene Expression in Cells and in an In Vivo Model of Pancreatic Cancer.
The Potent G-Quadruplex-Binding Compound QN-302 Downregulates S100P Gene Expression in Cells and in an In Vivo Model of Pancreatic Cancer.
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DOI：
10.3390/molecules28062452
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发表时间：
2023-03-07
期刊：
影响因子：
--
通讯作者：
Neidle S
中科院分区：
文献类型：
--
作者：
Ahmed AA;Greenhalf W;Palmer DH;Williams N;Worthington J;Arshad T;Haider S;Alexandrou E;Guneri D;Waller ZAE;Neidle S
萘二酰亚胺化合物QN-302被设计成与癌症相关基因的启动子区域内的G-四链体DNA序列结合，在胰腺癌细胞系中具有高抗增殖活性，并且在该疾病的几种实验模型中具有抗肿瘤活性。我们在这里表明，QN-302也导致S100 P基因和S100 P蛋白在细胞和体内的表达下调。这种蛋白质被公认为参与几种人类癌症的关键增殖和运动途径，并已被鉴定为胰腺癌的潜在生物标志物。S100 P基因含有60个推定的四链体形成序列，其中之一是在启动子区，48个核苷酸上游的转录起始位点。我们报告的生物物理和分子模拟研究表明，该序列在体外形成高度稳定的G-四链体，QN-302进一步稳定。我们还报告了转录组分析，显示S100 P表达在人胰腺癌肿瘤组织中高度上调，与正常胰腺材料相比。上调的程度取决于肿瘤细胞的分化程度，来自更晚期疾病的分化最差的肿瘤细胞具有最高水平的S100 P表达。实验药物QN-302目前处于IND前开发阶段（截至2023年第1季度），其下调S100 P蛋白表达的能力支持该蛋白作为胰腺癌治疗反应标志物的作用。这些结果也与以下假设一致：S100 P启动子G-四链体是QN-302在转录水平上的胰腺癌的潜在治疗靶点。
The naphthalene diimide compound QN-302, designed to bind to G-quadruplex DNA sequences within the promoter regions of cancer-related genes, has high anti-proliferative activity in pancreatic cancer cell lines and anti-tumor activity in several experimental models for the disease. We show here that QN-302 also causes downregulation of the expression of the S100P gene and the S100P protein in cells and in vivo. This protein is well established as being involved in key proliferation and motility pathways in several human cancers and has been identified as a potential biomarker in pancreatic cancer. The S100P gene contains 60 putative quadruplex-forming sequences, one of which is in the promoter region, 48 nucleotides upstream from the transcription start site. We report biophysical and molecular modeling studies showing that this sequence forms a highly stable G-quadruplex in vitro, which is further stabilized by QN-302. We also report transcriptome analyses showing that S100P expression is highly upregulated in tissues from human pancreatic cancer tumors, compared to normal pancreas material. The extent of upregulation is dependent on the degree of differentiation of tumor cells, with the most poorly differentiated, from more advanced disease, having the highest level of S100P expression. The experimental drug QN-302 is currently in pre-IND development (as of Q1 2023), and its ability to downregulate S100P protein expression supports a role for this protein as a marker of therapeutic response in pancreatic cancer. These results are also consistent with the hypothesis that the S100P promoter G-quadruplex is a potential therapeutic target in pancreatic cancer at the transcriptional level for QN-302.
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影响因子：
6.2
作者：
Dakhel, S.;Padilla, L.;Adan, J.;Masa, M.;Martinez, J. M.;Roque, L.;Coll, T.;Hervas, R.;Calvis, C.;Messeguer, R.;Mitjans, F.;Hernandez, J. L.
通讯作者：
Hernandez, J. L.
DOI：
10.1038/nrg3296
发表时间：
2012-11
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
DOI：
10.3390/diagnostics10121056
发表时间：
2020-12-06
期刊：
Diagnostics (Basel, Switzerland)
影响因子：
--
作者：
Ideno N;Mori Y;Nakamura M;Ohtsuka T
通讯作者：
Ohtsuka T
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
--
作者：
Ricci, Vincenzo;Fabozzi, Teresa;Bareschino, Maria Anna;Barletta, Emiddio;Germano, Domenico;Paciolla, Immacolata;Tinessa, Vincenza;Grimaldi, Antonio Maria
通讯作者：
Grimaldi, Antonio Maria