A Phenotypic Approach to the Discovery of Potent G-Quadruplex Targeted Drugs

被引:6
|
作者
Neidle, Stephen [1 ]
机构
[1] UCL, Sch Pharm, London WC1N 1AX, England
来源
MOLECULES | 2024年 / 29卷 / 15期
基金
英国医学研究理事会; 英国惠康基金;
关键词
quadruplex DNA; pancreatic cancer; phenotypic screening; QN-302; structure-based design; STRUCTURE-BASED DESIGN; TELOMERIC G-QUADRUPLEXES; SMALL-MOLECULE; PANCREATIC-CANCER; C-MYC; ANTIPROLIFERATIVE ACTIVITY; STRUCTURAL BASIS; PROMOTER REGION; DNA STRUCTURES; IN-VIVO;
D O I
10.3390/molecules29153653
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:22
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