Rational drug design of G-quartet DNA as anti-cancer agents.
The ability of certain DNA sequences to form G-quartet structures has been exploited recently to develop novel anti-cancer agents including small molecules that promote G-quartet formation within the c-MYC promoter thereby repressing c-MYC transcription and introducing G-quartet-forming oligodeoxynucleotides (GQ-ODN) into cancer cells resulting in p53-dependent cell cycle arrest and inhibition of DNA replication. GQ-ODNs also have been developed as potent inhibitors of signal transducer and activator of transcription (STAT) 3, a critical mediator of oncogenic signaling in many cancers. This review summarizes the rational design of G-quartet forming DNA drugs as Stat3 inhibitors. Topics that are reviewed include the strategy of structure-based drug design, establishment of a structure-activity relationship, development of a novel intracellular delivery system for G-quartet-forming DNA agents and in vivo drug testing to assess the anti-cancer effects of DNA drugs in tumor xenografts. Results to date with GQ-ODN targeting Stat3 are encouraging, and it is hoped that continued pursuit of the methodology outlined here may lead to development of an effective agent for treatment of metastatic cancers, such as prostate and breast, in which Stat3 is constitutively activated.
Jing
Naijie
N
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. njing@bcm.tmc.edu
Sha
Wei
W
Li
Yidong
Y
Xiong
Weijun
W
Tweardy
David J
DJ
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D015195:Drug Design; D006801:Humans; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000138:chemical synthesis* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009841:Oligonucleotides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators