Breast cancer is the most frequently diagnosed malignancy in women, with metastatic disease accounting for the majority of mortality. Aberrant fibroblast growth factor receptor 1 (FGFR1) signalling is a key driver of breast cancer progression and therapy resistance, yet FGFR1-amplified tumours show limited response to current FGFR-targeted inhibitors due to toxicity and kinase-independent functions. Recent evidence demonstrates that FGFR1 expression is transcriptionally regulated by G-quadruplex (G4) DNA structures within its promoter, opening new avenues for epigenetic intervention. However, selective targeting of individual G4s remains challenging due to their widespread genomic distribution.
This project aims to develop a cellular structural biology strategy to selectively repress FGFR1 transcription by stabilizing its promoter G4 using dual DNA-binding conjugates. The objectives are to (i) structurally characterize FGFR1 promoter G4s in vitro and in living cells, (ii) quantitatively assess interactions between G4s and stabilizing ligands, (iii) design and biologically validate selective dual DNA-binding conjugates and evaluate their effects on FGFR1 transcription in cells, and (iv) elucidate the molecular recognition mechanism of conjugate–G4 complexes by NMR.
The research integrates in vitro biophysical characterization with in-cell validation using high-field solution and in-cell NMR, complemented by surface plasmon resonance, calorimetry, and cell-based reporter assays. Dual DNA-binding conjugates will be rationally designed, synthesized, and functionally evaluated, and lead candidates will be structurally resolved by NMR.
Hosted at CEITEC MU within the Non-Coding Genome research group, the project is fully aligned with the CEIPEX Structural Biology domain. It exploits CEITEC’s cutting-edge infrastructure to bridge structural biology, chemical biology, and cancer research, advancing structure-guided epigenetic strategies with translational potential for FGFR1-driven cancers.