A new strategy for detection and development of tractable telomerase inhibitors.

Despite intense academic and industrial efforts and innumerable in vitro and cell studies, no small-molecule telomerase inhibitors have emerged as drugs. Insufficient understanding of enzyme structure and mechanisms of interdiction coupled with the substantial complexities presented by its dimeric composition have stalled all progress toward small-molecule therapeutics. Here we challenge the assumption that human telomerase provides the best platform for inhibitor development by probing a monomeric Tetrahymena telomerase with six tool compounds. We find BIBR-1532 (2) and MST-312 (5) inhibit only human telomerase, whereas β-R (1), THyF (3), TMPyP4 (6), and EGCG (4) inhibit both enzymes. Our study demonstrates that some small-molecule scaffolds can be easily surveyed with in vitro studies using Tetrahymena telomerase, a finding that could lead to more tractable inhibitors with a greater potential for development given the more precise insights that can be gleaned from this more easily expressed and assayed monomeric enzyme.