# Targeting telomerase for melanoma therapeutics

> **NIH NIH R01** · WISTAR INSTITUTE · 2020 · $471,448

## Abstract

PROJECT SUMMARY
Highly recurrent TERT (the catalytic subunit of telomerase) promoter mutations in human familial and sporadic
melanoma lead to a 2-4 fold increase in TERT transcription and telomerase activation, making telomerase an
attractive target for melanoma cancer therapies. The development of effective small-molecule inhibitors of
telomerase has been hindered by the lack of high-resolution structural data on telomerase. We used the TERT
structure determined by X-ray crystallography to screen >500,000 compounds by in silico methods. This
approach allowed us to identify a set of small molecules containing a similar scaffold that inhibited the
enzymatic activity of telomerase. We have obtained the X-ray co-crystal structure of TERT bound to one of
these compounds, revealing a novel and unexpected allosteric binding site, namely the FVYL pocket, located
on the surface of the TERT thumb domain. This is the first-ever ligand-TERT co-crystal structure that has been
solved to date. Using biochemical assays, we showed that the FVYL pocket binds telomerase RNA (TER),
and therefore our initial lead acts by inhibiting the TERT – TER association and telomerase RNP assembly.
We have also found compounds that can selectively inhibit the growth of telomerase-positive human
melanoma cell lines, but show little growth inhibition of telomerase negative cancer and non-transformed cells
in culture. The previous telomerase inhibitor BIBR-1532 was also examined. We determined the BIBR-1532-
TERT co-crystal structure, showing that it binds to the same general area, but in a slightly different manner, as
do the ligands that we identified by computational prescreening. We also found that BIBR-1532 had
substantially less efficacy with a delayed action at killing melanoma cells than does the top hit from our own
studies. The aims of this proposal are to (A) use structure-based design methods combined with medicinal
chemistry to improve potency for the inhibition of telomerase, (B) evaluate the biochemical activity and
specificity for telomerase while investigating the cellular pathways perturbed on telomerase inhibition, and (C)
probe the in vivo melanoma oncolytic activity of the telomerase inhibitors. We are uniquely positioned to
accomplish the work described because of our ability to iteratively obtain additional ligand-TERT co-crystal
structures, and our expertise in the rapid parallel synthesis of new compound libraries, taking advantage of
>20,000 reagents and starting materials available onsite (>800 boronic acids). Our research may provide a
new approach for the structure-based design of small-molecule inhibitors of telomerase, and may reinvigorate
research in the area of small-molecule telomerase inhibitors, eventually resulting in new drugs to treat
melanoma alone or in combination with existing chemo- or immunotherapies. The research team is led by an
expert in telomerase (Skordalakes) at The Wistar Institute, along with experienced pharma researchers in
...

## Key facts

- **NIH application ID:** 9981663
- **Project number:** 5R01CA201312-05
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Emmanuel Skordalakes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $471,448
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981663

## Citation

> US National Institutes of Health, RePORTER application 9981663, Targeting telomerase for melanoma therapeutics (5R01CA201312-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9981663. Licensed CC0.

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