Sequences in the HSP90 promoter form G-quadruplex structures with selectivity for disubstituted phenyl bis-oxazole derivatives.
The HSP90 protein is an important target in cancer. We report here that stable quadruplex DNAs can be formed from a promoter sequence in the HSP90 gene, on the basis of melting, circular and NMR studies, and show that these can be selectively targeted by non-macrocyclic quadruplex-stabilizing phenyl bis-oxazole derivatives. These do not bind significantly to duplex DNA and show low stabilization of the human telomeric quadruplex. These results suggest an approach to targeting HSP90 at the DNA level.
CRUK Biomolecular Structure Group, UCL School of Pharmacy, 29-39 Brunswick Square, WC1N 1AX London, United Kingdom.
Stephan A
SA
Ohnmacht
Marialuisa
M
Micco
Vanessa
V
Petrucci
Alan K
AK
Todd
Anthony P
AP
Reszka
Mekala
M
Gunaratnam
Marta A
MA
Carvalho
Mire
M
Zloh
Stephen
S
Neidle
D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D054856:G-Quadruplexes; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D013329:Structure-Activity Relationship; D016615:Telomere / Q000737:chemistry
D018841:HSP90 Heat-Shock Proteins; D047028:Macrocyclic Compounds; D010080:Oxazoles; D004247:DNA