# Bioinspired chemical probe approach targeting telomerase reverse transcriptase

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $397,571

## Abstract

PROJECT SUMMARY
Telomerase has attracted significant attention as a potential target for understanding the aging process and for
the treatment of cancer, since telomeres and telomerase have important roles in the transformation and
survival of cancer cells. Previous prevailing strategies for targeting telomerase were based on the assumption
that in cancer cells, telomere-length maintenance was the sole pro-survival function of this assembly. However,
increasingly evidence strongly indicates that a) inhibition of the telomere-lengthening activity of telomerase is
not a magic bullet treatment for cancer, and b) there is a much larger role for telomerase in key cellular
pathways and these functions are not well understood. Although there have been promising clinical candidates
among telomerase inhibitors, the translation of telomerase-targeted therapies to the clinic remains elusive and
frustratingly slow. This lack of progress is due in part to the growing list of unanswered questions surrounding
telomerase and its role in cancer biology; notably, that hTERT has non-canonical functions separate from
its telomere-lengthening activity that are linked to cancer cell survival. This proposal builds on the
collaboration between the Scheidt and Kron research groups to bring our expertise in chemical synthesis and
cancer biology to bear on key gaps in the knowledge surrounding hTERT, its non-canonical functions, and its
involvement in cancer cell survival. We have discovered that small molecules based on the natural product
chrolactomycin inhibit telomerase and provide a unique platform for probe development. Based on robust
chemical and biological results, we propose to first develop enhanced small molecule probes with improved
efficacy. These compounds will enable precise covalent modification of hTERT catalytic function without
perturbing the overall complex assembly. The following Aims will focus on exploring the use of these new tools
to explore the role(s) of telomerase in DNA damage repair and cell senescence through in-depth analysis of
multiple functions of telomerase as a buffer of cell stress and determinant of cell immortality. The long-term
goal of this project is to understand and leverage the molecular basis for how these natural product-based
molecular tools impact the telomere lengthening and most importantly, non-canonical functions of hTERT.
Ultimately, this new knowledge will drive the development of new understanding of telomerase and its
biological roles.

## Key facts

- **NIH application ID:** 10071461
- **Project number:** 1R01CA254047-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Stephen J. Kron
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,571
- **Award type:** 1
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071461

## Citation

> US National Institutes of Health, RePORTER application 10071461, Bioinspired chemical probe approach targeting telomerase reverse transcriptase (1R01CA254047-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10071461. Licensed CC0.

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