Development of Chemical Probes for CREBBP

Lead Research Organisation: University of Oxford
Department Name: Interdisciplinary Bioscience DTP

Abstract

CREBBP is an important transcriptional coactivator that can affect the functions of multiple cellular pathways. It comprises 9 domains, which enable it to bind to >400 partner proteins. One such domain is the bromodomain, which is viewed as an epigenetic 'reader' domain as it binds to acetyl-lysine residues on many proteins, including histones. CREBBP also possesses a lysine acetyl transerfase (KAT) domain, which 'writes' the epigenetic code, as it transfers an acetyl group to target proteins, including histones. Small molecule probes that inhibit the function of some of CREBBP's domains have been reported, and they are helping to elucidate the many important cellular roles of CREBBP. Tools that act as a chemical 'knock-down' of the whole protein would also have significant value in these investigations.

PROteolysis TArgeting Chimera (PROTAC) chemical probes can be used to fully remove a protein from the cell, meaning its overall cellular function can be studied. PROTACs hijack the natural proteasome-dependant degradation pathway in the cell to effect degradation of the protein of interest (POI). PROTACs are bifunctional molecules, which comprise a ligand for the POI coupled to a ligand for an E3 ubiquitin ligase ligand via a linker. The PROTAC functions by holding these two proteins in close proximity. The E3 ligase associates with an E2 ubiquitin ligase, and one of these proteins iteratively adds ubiquitin to the POI. The polyubiquitinated POI is then recognised by the proteasome where it is degraded. The change in cellular mechanisms that result from the deletion of the target protein can then studied.

We propose to use existing CREBBP ligands coupled to E3 ubiquitin ligase ligands to develop PROTACs that will degrade the whole CREBBP protein. These tool compounds will be of great use in our continuing studies of CREBBP function.

This project falls within the BBSRC priority areas of "healthy ageing across the life course", "synthetic biology" and "technology development for the biosciences".

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/S507003/1 01/10/2018 31/12/2022
2110826 Studentship BB/S507003/1 01/10/2018 30/06/2023