CH41

CH41 is a first-in-class small molecule inhibitor of Chromodomain Helicase DNA Binding Protein 4 (CHD4), the catalytic core of the Nucleosome Remodeling and Deacetylase (NuRD) complex. It acts by covalently engaging cysteine residues within the CHD4 chromodomain, which leads to the stabilization of CHD4 on chromatin—a mechanism referred to as chromatin trapping. This binding blocks the chromatin remodeling activity of CHD4 and subsequently induces the dissociation and proteasomal degradation of the NuRD complex. By disrupting CHD4's interactions with key partners such as ZMYND8 and RBBP4/7, CH41 represses RAD51 expression and impairs homologous recombination-mediated DNA repair. This mechanism effectively re-sensitizes temozolomide-resistant glioblastoma cells to treatment by increasing the accumulation of DNA damage markers like γH2AX and 53BP1.