The group has a long-standing interest in the development of small molecule probes that enable investigation into a certain biological system. We reported some of the first ligands for the bromodomain and extra terminal domain (BET) family of bromodomain-containing proteins, and  the first high affinity ligands for the CREBBP/P300 bromodomains. We have also investigated the role of bromodomains in disease causing parasites, including Schistosoma mansoni, Leishmania, and Trypanosoma cruzi.

Key publications:

Schiedel, McArdle, et al. J. Med. Chem., 2023, 66, 15801.

Brand et al. J. Med. Chem., 2021, 64, 10102.

Rooney et al. Angew. Chem. Int. Ed., 2014, 53, 6126.

Hewings et al. J. Med. Chem., 2013, 56, 3217.

Hewings, et al. J. Med. Chem., 2011, 54, 6761. 

Hypoxia (lower than normal levels of oxygen) is a characteristic of solid tumors that causes resistance to chemo- and radiotherapy, and worsens patient prognosis. The lack of oxygen in tumors alters the chemical environment within tumor cells, providing an opportunity for imaging and targeting regions of hypoxia. We have harnessed the reducing tumor environment to develop pro-drugs that selectively release their active agents in hypoxia. We have also developed new tools to enable imaging of hypoxia and the tumor microenvironment.

Key publications:

Tosun et al. JACS Au, 2023, 3, 3237.

Wallabregue et al. J. Am. Chem. Soc., 2023, 145, 2572.

Skwarska et al. Cell Chem. Biol., 2021, 28, 1258.

O’Connor et al. ACS Cent. Sci., 2017, 3, 20.

Costa et al. Science, 2017, 355, 170.

O’Connor et al. Nat. Protoc., 2016, 11, 781.

We have an interest in developing chemical probes that function by inducing proximity between two proteins so as to alter their function. Our initial work in this area has focused on taking a 'bump-and-hole' approach to the development of small molecular immunomodulatory drugs (IMiDs) that selectively bind to an engineered degron (derived from a zinc finger), leading to protein degradation. This IMiD-degron pair can be used to selectively degrade proteins of interest that are fused to the degron, without affecting endogenous proteins. This technology has broad application in cell biology and target validation.

Key publications:

Brennan et al. bioRxiv preprint, DOI: https://doi.org/10.1101/2024.03.15.585309.