Structure-based discovery of chromatin remodeling inhibitors

The proposed research aims to accelerate the discovery of small molecule inhibitors targeting CHD1, a chromatin remodeler implicated in the maintenance of genomic stability and the progression of highly proliferative cancers, particularly PTEN-deficient prostate cancers. Building upon pioneering structural work, we will employ a multi-faceted approach to identify and characterize potential therapeutic compounds.

First, we will leverage our cryo-EM structures of CHD1 to perform a comprehensive virtual screen, utilizing identified small molecule binding sites to guide the selection of candidate compounds (Aim 1). To facilitate rapid evaluation of these compounds, we will develop a high-throughput FRET-based nucleosome sliding assay (Aim 2), complementing existing biochemical assays. This powerful combination of assays will enable us to assess the effects of the identified compounds on both CHD1's enzymatic activity and its biological function in nucleosome sliding. Promising compounds will undergo rigorous characterization, including specificity testing against a panel of related chromatin remodelers and structural studies to elucidate their binding modes (Aim 3). The structural insights gained will inform the design of optimized compounds, ultimately yielding potent and specific CHD1 inhibitors for use in cell-based studies and as therapeutic agents in PTEN-deficient cancers. By integrating cutting-edge structural biology, virtual screening, and high-throughput biochemical assays, this project will not only advance our understanding of CHD1's role in cancer but also lay the foundation for the development of novel chromatin remodeling-targeted therapies. The identification of CHD1 inhibitors holds great promise for the treatment of aggressive, rapidly proliferating cancers, addressing a critical unmet need in oncology.