Epigenetic information is encoded in a wide range of histone modifications, which gives rise to the “histone code” and brings an additional level of complexity to the control of gene expression. The proteins involved include “writers”, “erasers”, and “readers”, which install, remove and recognise histone modifications, respectively. Given the implication of epigenetics in diseases, including cancer, epigenetic regulation presents opportunities for the development of novel therapeutics. Understanding the roles of proteins involved in epigenetic regulation is, therefore, important. TRIM33 is a transcription regulator with E3 ubiquitin ligase activity and has been associated with leukaemia and DNA damage response pathways. It contains a tandem PHD finger-bromodomain cassette, which recognise methylated and acetylated lysine residues on histone proteins, respectively. This project aims to develop ligands for the TRIM33 bromodomain, which can be used as chemical probes to further validate the role of TRIM33. Initial screening identified a hit TRIM33 bromodomain ligand that has since been validated and used as the starting point for further development. A combination of biological assay techniques and computational studies have been used to guide the investigation of the acetyl-lysine-binding pocket. Iterations of synthesis and testing have led to the development of a binder with an IC50 of 2 µM. Ongoing work is focused on synthesising analogues and further exploring the structure-activity relationships (SAR) around the benzimidazolone core.

Development of chemical probes for the TRIM33 bromodomain

256th National Meeting (2018)

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