BRITE-338733: From RecA inhibition to cancer treatment

ATP-dependent chromatin remodelers play an important role in regulating cellular processes by modulating the chromatin structure. Despite their significance, the ATPase domains within the catalytic subunit of these remodelers remain not extensively explored as a therapeutic target. The aim of this study is to identify computationally and validate experimentally novel inhibitors of the ATP hydrolysis activity in the RSC chromatin remodeler, by binding to its ATP binding pocket and/or to DNA. Following an initial screening through docking studies, a list of five compounds were selected for a detailed analysis. Based on molecular dynamics simulations, BRITE-338733 was highlighted as the most promising candidate. This result was supported experimentally with ATP hydrolysis assays, where the BRITE-338733 stood as the compound that demonstrated significant inhibition. Furthermore, both computational and experimental analyses showed that BRITE-338733 binds strongly to DNA. Additionally, BRITE-338733 demonstrated cytotoxicity against breast cancer cells, suggesting its potential as an anticancer therapeutic.