tailieunhanh - Báo cáo khoa học: Human telomeric G-quadruplex: The current status of telomeric G-quadruplexes as therapeutic targets in human cancer

Telomeres play an important role in cellular aging and cancer. Human telomeric DNA and RNA G-rich sequences are capable of forming a four-stranded structure, known as the G-quadruplex. Such a structure might be important for telomere biology and a good target for drug design. | MINIREVIEW Human telomeric G-quadruplex The current status of telomeric G-quadruplexes as therapeutic targets in human cancer Stephen Neidle Cancer Research UK Biomolecular Structure Group University of London UK Keywords acridine anticancer drug drug-like in vivo medicinalchemistry pharmacology quadruplex telomerase telomere Correspondence Stephen Neidle Cancer Research UK Biomolecular Structure Group The School of Pharmacy University of London 29-39 Brunswick Square London WC1N 1AX UK Fax 44 207 753 5970 Tel 44 207 753 5969 E-mail The 3 -ends of human chromosomal DNA terminate in short singlestranded guanine-rich tandem-repeat sequences. In cancer cells these are associated with the telomere-maintenance enzyme telomerase together with the end-binding protein hPOT1. Small molecules that can compete with these proteins and induce the single-stranded DNA to form quadruplex-ligand complexes are in effect able to expose these 3 -ends which results in the activation of a DNA damage response and selective inhibition of cell growth. Several of these G-quadruplex binding molecules have shown promising anticancer activity in tumour xenograft models which indicate that the approach may be applicable to the treatment of a wide range of human cancers. This minireview summarizes the available data on these compounds and the challenges posed for drug discovery. Received 25 June 2009 revised 5 October 2009 accepted 6 October 2009 doi Introduction Human telomeres comprise tandem repeats of the DNA motif TTAGGG together with associated telomeric proteins 1-3 as well as other more transiently associated DNA-repair and damage-response proteins such as Ku 4 . The terminal 150-250 nucleotides at the extreme 3 -ends of telomeres are single-stranded 5 but are protected from higher order aggregation by binding to multiple repeats of a single-stranded DNA binding protein hPOT1 in humans which in turn interacts with other .