Tripartite motif-containing (TRIM) protein 33 possesses a tandem bromodomain and PHD finger at its C-terminus, and is involved in the PARP-dependent DNA damage repair pathway. The development of TRIM33 bromodomain ligands will help validate the concept that TRIM33 inhibitors will be synthetically lethal in situations where DNA damage is increased, similar to PARP inhibitors. Based on a TRIM33 AlphaScreenTM, a bromodomain ligand possessing a benzimidazolone core as the acetyl-lysine mimic (TRIM33α IC50 = 4.22 μM; TRIM33β IC50 = 10.6 μM) was identified. This project has explored a diverse range of related analogues, using docking and molecular dynamics to guide design. A combination of AlphaScreenTM and WaterLOGSY NMR experiments have been used to evaluate binding. Extensive investigation has led to a deeper understanding of the key structural features of the TRIM33 bromodomain binding pocket and has resulted in the development of a ligand (TRIM33α IC50 = 2.48 μM; TRIM33β IC50 = 7.08 μM) which is selective over close relative TRIM24, and also BRD4. This project also explores targeted protein degradation of TRIM33 using proteolysis-targeting chimeras (PROTACs) to unveil the function of the whole protein. The TRIM33 bromodomain ligands will be linked to an E3 ubiquitin ligase warhead to recruit TRIM33 to the E3 ligase cereblon. The synthesis of the TRIM33 ligand and E3 ligase binding moiety with appropriate functional handles allows diversification of the linker to enable rapid optimisation. The development of ligands for the bromodomain of TRIM33 in parallel with PROTACs for TRIM33 will highlight the differences between inhibition of the bromodomain and degradation of the whole protein, and thus reveal the relevance of TRIM33 and its bromodomain in disease.

Chemical tools to probe the function of TRIM33

2019 Spring National Meeting

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