Lead Discovery Center GmbH, Nordrhein-Westfalen, Germany
Abstract: Mutations in RECQ helicases (BLM, WRN, RECQ4, and RECQ1) result in autosomal recessive disorders characterized by chromosomal instability and cancer risk. In addition, mutations in Fe-S cluster-containing DNA helicases (XPD, FANCJ, RTEL1 & DDX11) contribute to cancer development. In cancer, DNA helicase expression is usually upregulated, leading to an increase in DNA repair transactions. Helicases are an emerging drug target family for which selective inhibitors are highly sought after.
We have developed a technology platform integrating biochemical, biophysical, and cellular assays. This platform is designed to discover selective small molecule helicase inhibitors, serving as a foundational step for drug development and as tools to elucidate helicase biology. Our work is conducted within a consortium of premier European academic and commercial helicase research labs. We have entered seven helicases into our platform and screened up to 330,000 small molecules. Results highlight a significant correlation between validated hits' potency across biochemical, phenotypic, and biophysical assays. Currently, SAR (Structure-Activity Relationship) and H2L (Hit-to-Lead) programs are underway to enhance the potency of these validated hits.