Telomeres are repetitive nucleic acid sequences located at chromosome termini that preserve genomic stability by preventing degradation, recombination, and chromosomal end fusion.1 Progressive telomere shortening occurs during normal cell division; however, approximately 10–15% of cancers maintain telomere length through the Alternative Lengthening of Telomeres (ALT) pathway, a recombination-based mechanism that enables continued proliferation independent of telomerase.1,2 The FANCM-RMI interaction is essential to suppress ALT-associated toxicity by reducing replication stress at telomeres, indicating that it is a promising therapeutic target in ALT-positive cancers.2
This project focuses on validation and preliminary SAR studies on small molecules identified from a high-throughput screen of 300,000 compounds at the National Drug Discovery Centre. Around 60 candidate compounds were purchased for initial validation, using a competitive fluorescence polarisation assay to assess in vitro target binding. Top-performing analogues were repurified and resynthesised to eliminate potential interference from impurities, revealing that most apparent binding events were the result of false positive signals. Evaluation of inactive analogues associated with computational-based modelling has provided preliminary structure–activity relationship insights and clarified structural features that influence target engagement.