# Deciphering the structure and dynamics of non-canonical DNA implicated in cancer

> **NIH NIH R15** · SWARTHMORE COLLEGE · 2020 · $431,986

## Abstract

PROJECT SUMMARY
The proposed research will improve the selectivity and efficacy of anticancer therapies by contributing new
knowledge about non-canonical nucleic acid structures, G-quadruplexes (GQ) and i-motifs, and details of their
interactions with small-molecule ligands. Bioinformatics studies have identified 700,000 sequences with GQ-
forming potential in the human genome. The C-rich opposite strands are proposed to form i-motifs. There is now
convincing biological evidence that GQs and i-motifs form in vivo and that these structures complement each
other in regulating a variety of cancer-related biological processes. GQ nucleic acids have been firmly
established as an important therapeutic target for cancer. The same evidence for i-motifs is steadily
accumulating. Small molecules that bind selectively to GQ DNA and RNA and to i-motifs have been identified,
and some have been shown to inhibit tumor cells growth; however, exact mechanisms underlying this inhibition
are not known. Additionally, the number of selective i-motif ligands is low. Such ligands may ultimately become
lead compounds for cancer intervention superior to conventional mutagenetic therapies.
Nucleic acid-centered drug discovery programs suffer from limited structural information for GQs and i-motifs,
especially in the presence of ligands. As of now, no structure of an i-motif-ligand complex has been reported.
The situation is further complicated by high structural diversity of both GQs and i-motifs, their contradictory
biological functions, and our limited ability to target their specific folding topology (e.g., parallel vs antiparallel
GQs).
To address these challenges, we propose to perform comprehensive crystallographic investigation of telomeric
and oncogene promoter GQs and i-motifs, both alone and in complex with novel and commercially available
selective small-molecule ligands. The diversity of interactions which provide stability to GQs and i-motifs will be
determined. The details of ligand binding sites, as well as chemical and structural features of ligands essential
for their affinity and selectivity will be identified. This work will be complemented by spectroscopic and
calorimetric studies of the thermodynamic parameters of ligand binding. For GQ DNA, that is much more
explored, structural studies will be complemented by rigorous kinetic exploration of ligand-assisted GQ folding.
Kinetic information can help us identify the timescale of GQ formation and, thus, biological processes that can
be affected by the presence of these structures. Collectively, the proposed work will enhance our understanding
of GQ and i-motif structural plasticity, supply coordinates for drug discovery platforms, shed light on the origin of
ligand selectivity for a specific DNA or RNA target, and guide the design of novel anticancer therapies all while
providing transformative training to Swarthmore undergraduates.

## Key facts

- **NIH application ID:** 10046709
- **Project number:** 1R15CA253134-01
- **Recipient organization:** SWARTHMORE COLLEGE
- **Principal Investigator:** Liliya A Yatsunyk
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $431,986
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046709

## Citation

> US National Institutes of Health, RePORTER application 10046709, Deciphering the structure and dynamics of non-canonical DNA implicated in cancer (1R15CA253134-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10046709. Licensed CC0.

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