About the Project
Tumour heterogeneity poses a significant hindrance to effective cancer therapy, as response to all modalities of treatment is disparate. One of the best described sources of tumour heterogeneity is oxygenation levels, which varies dramatically in solid tumours and gives to rise to areas with insufficient oxygen (hypoxia). Tumour cells which survive and adapt to hypoxia represent the most aggressive and most therapy-resistant fraction of the tumour. The Conway and Hammond groups are focused on both the study of the biological mechanisms which allow cells to tolerate hypoxia, and also the identification of novel strategies to target these cells (Olcina et al., 2013 Cazares-Korner et al., 2013). BET bromodomain inhibitors have recently been described and importantly have been shown to have anti-tumour activity due to a number of biological roles (Hewings et al.,2013). This project will focus on the consequences of BET bromodomain inhibition in the context of tumour hypoxia, and/or the targeting of these ligands to regions of hypoxia. Applications are welcome from 1) biologists interested in studying the biological consequences of BET inhibition, for example roles in transcription, replication, and cell viability, or 2) chemists interested in developing hypoxia-activated BET bromodomain inhibitors to specifically target hypoxic cancers (O’Connor et al., 2016).
References
Cazares-Körner C, Pires IM, Swallow ID, Grayer SC, O'Connor LJ, Olcina MM, Christlieb M, Conway SJ, Hammond EM. CH-01 is a hypoxia-activated prodrug that sensitizes cells to hypoxia/reoxygenation through inhibition of Chk1 and Aurora A. ACS Chem Biol. 2013
Hewings DS, Fedorov O, Filippakopoulos P, Martin S, Picaud S, Tumber A, Wells C, Olcina MM, Freeman K, Gill A, Ritchie AJ, Sheppard DW, Russell AJ, Hammond EM, Knapp S, Brennan PE, Conway SJ. Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands. J Med Chem. 2013
Olcina MM, Foskolou IP, Anbalagan S, Senra JM, Pires IM, Jiang Y, Ryan AJ, Hammond EM. Replication stress and chromatin context link ATM activation to a role in DNA replication. Mol Cell. 2013
O'Connor LJ, Cazares-Körner C, Saha J, Evans CN, Stratford MR, Hammond EM, Conway SJ. Design, synthesis and evaluation of molecularly targeted hypoxia-activated prodrugs. Nat Protoc. 2016