Telomere inhibition and telomere disruption as processes for drug targeting.
The components and cofactors of the holoenzyme telomerase and its substrate telomeric DNA are attractive targets for anticancer agents that act by inhibiting the activity of telomerase. This review outlines recent advances in telomerase inhibition that have been achieved using antisense oligonucleotides and ribozymes that target the telomerase mRNA or its hTR RNA template. Although these are potent catalytic inhibitors of telomerase, they are challenging to implement in the clinic due to their delayed effectiveness. Drugs that directly bind to the telomeres, the complex structures that are associated at the telomeric ends, and stabilize secondary DNA structures such as G-quadruplexes are also potent inhibitors of telomerase. Special focus is given here to the telomeres, the biological machinery that works in tandem with telomerase to elongate telomeres, the causes of telomere disruption or dysfunction, and the consequences of disruption/dysfunction on the activity and design of anticancer agents.
Rezler
Evonne M
EM
College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, USA. rezler@pharmacy.arizona.edu
Bearss
David J
DJ
Hurley
Laurence H
LH
D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000187:drug effects* / Q000378:metabolism
D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; D019098:Telomerase