Rick Betori
Northwestern
Telomerase is a ribonucleoprotein enzyme that lengthens telomeres by catalyzing the addition of repetitive sequences of nucleotides to the 3′ ends of chromosomes. Because telomerase activity counteracts the shortening of telomeres, telomerase inhibition has attracted significant recent interest as a promising strategy for understanding and counteracting neoplasticity and cancer.
A promising approach for telomerase inhibition is to develop small molecules to target the active site of human telomerase reverse transcriptase (hTERT), the catalytic protein subunit of telomerase. The natural product chrolactomycin, which inhibits telomerase, serves as a structural basis for the development of simplified, optimized novel hTERT inhibitors. Using computer-aided design to obtain insight into the docking of chrolactomycin in the binding site of hTERT, a series of structures were designed that maintain important recognition interactions similar to chrolactomycin while possessing synthetically tractable structures and favorable pharmacokinetic properties. This library has been evaluated for hTERT inhibition, and Activity Based Proteomics Profiling to determine compound selectivity in vitro. Fluorescent labeling has enabled the elucidation of changes to the subcellular location of hTERT across the cell cycle and during cellular response to various stimuli, as well as identify the location of the assembly of the telomerase complex prior to and upon binding to the telomere.
Overall, the development of new small molecule telomerase inhibitors will expand the toolkit available for the investigation of telomerase. We anticipate that these structures will be useful molecular probes to understand the active site and binding properties of hTERT, as well as examining the effect of hTERT inhibition on non-canonical pathways. The answers that these activities will provide will greatly understand our fundamental understanding of telomerase and will have significant potential to impact human health.
A promising approach for telomerase inhibition is to develop small molecules to target the active site of human telomerase reverse transcriptase (hTERT), the catalytic protein subunit of telomerase. The natural product chrolactomycin, which inhibits telomerase, serves as a structural basis for the development of simplified, optimized novel hTERT inhibitors. Using computer-aided design to obtain insight into the docking of chrolactomycin in the binding site of hTERT, a series of structures were designed that maintain important recognition interactions similar to chrolactomycin while possessing synthetically tractable structures and favorable pharmacokinetic properties. This library has been evaluated for hTERT inhibition, and Activity Based Proteomics Profiling to determine compound selectivity in vitro. Fluorescent labeling has enabled the elucidation of changes to the subcellular location of hTERT across the cell cycle and during cellular response to various stimuli, as well as identify the location of the assembly of the telomerase complex prior to and upon binding to the telomere.
Overall, the development of new small molecule telomerase inhibitors will expand the toolkit available for the investigation of telomerase. We anticipate that these structures will be useful molecular probes to understand the active site and binding properties of hTERT, as well as examining the effect of hTERT inhibition on non-canonical pathways. The answers that these activities will provide will greatly understand our fundamental understanding of telomerase and will have significant potential to impact human health.