Proposed mechanism of action of 5-MeCITP for inhibiting telomerase activity.

(A) Pre-polymerization state of a natural telomerase substrate (dNTP). The two magnesium ions help to coordinate the nucleophilic attack of the 3′-OH of the terminal dNTP of the telomeric DNA strand on the α-phosphate group of the dNTP in the TERT active site. (B) Post-polymerization state of a natural telomerase dNTP substrate. The dNTP forms a Watson-Crick base pair with the RNA template to aid in nucleophilic attack of the phosphate backbone for incorporation into the synthesized DNA strand. (C) 5-MeCITP does not base pair appropriately with the RNA template, thereby occluding the RNA from the active site. As a consequence, 5-MeCITP is not incorporated into the DNA chain. dNTP, deoxynucleotide triphosphate; TERT, telomerase reverse transcriptase; 5-MeCITP, 5-methylcarboxyl-indolyl-2′-deoxyriboside 5′-triphosphate.