Scott Cohen

Dr Scott Cohen has been studying the biochemistry and structure of human telomerase since he joined Children's Medical Research Institute in 2003. Dr Cohen trained in organic chemical synthesis and biochemistry, obtaining his PhD in Chemistry from the prestigious California Institute of Technology (Caltech). He then moved to the University of Colorado to carry out Postdoctoral research in the laboratory of Nobel Laureate Professor Tom Cech, where he developed methods to produce semi-synthetic RNA enzymes (ribozymes) and study their structure and conformational dynamics. Dr Cohen’s expertise with RNA provided an excellent foundation for human telomerase, an RNA-protein enzyme complex.

Dr Cohen’s research program aims to develop potent and specific small-molecule telomerase inhibitors as potential cancer therapeutics. Essential to this endeavour has been establishing a foundation in telomerase purification, enzymology, and molecular structure. In 2015 Dr Cohen commenced high-throughput screening against a library of ~10⁵ small organic molecules and identified a potent small-molecule telomerase inhibitor. This compound displays nanomolar affinity (IC50) against purified telomerase in vitro; the compound has also been shown to inhibit telomerase within immortal cells.

Small-molecule telomerase inhibitor.
Small-molecule telomerase inhibitor. Purified human telomerase was assayed in vitro with a direct primer extension activity assay in the presence of increasing concentrations of inhibitor. Each product band progressing up the gel represents addition of one TTAGGG repeat onto the telomeric DNA substrate 5’-(TTAGGG)3-3’.

With the means to obtain highly pure telomerase Dr Cohen has been performing cryogenic electron microscopy (cryo-EM) to determine the 3D molecular structure of the enzyme, culminating with a 2.4 Angstrom structure of telomerase bound with its telomeric DNA substrate 5’-(TTAGGG)3-3’.

Structure of human telomerase catalytic core.
Structure of human telomerase catalytic core. 2.4 Angstrom EM map of the catalytic domain (left) and (right) close-up of dG-rC base pairs between the telomeric DNA substrate (green) and RNA template (blue), illustrating detail of the EM data (black mesh) and the corresponding model.

The next milestone will be to obtain a structure of telomerase bound with the small-molecule inhibitor, enabling structure-guided design, wherein 3D structure informs the location of inhibitor binding within the enzyme, and crucially, how the structure of the inhibitor can be modified through chemical synthesis to improve affinity (potency), specificity, and medicinal properties.