The development of hypoxia-activated probes for im.. (HYPOXPROBE)
The development of hypoxia-activated probes for imaging and therapy
Date du début: 1 nov. 2013,
Date de fin: 31 oct. 2015
Solid tumours contain hypoxic cells, which exist at a low oxygen tensions and are resistant to chemotherapy and radiotherapy. Although problematic for therapy, any quality that distinguishes tumour cells from healthy ones presents an opportunity for targeting therapies. We have begun developing prodrugs that selectively release inhibitors of cancer-related enzymes under hypoxia. In this project, we will develop hypoxia-activated inhibitors of the checkpoint kinase, Chk1, which is an important chemotherapeutic target. Allowing targeting of this compound to tumour cells. In addition, to enable imaging of hypoxic tumours we will develop novel hypoxia-activated fluorescent probes. The 2-nitroimidazole-based pimonidazole is a standard hypoxia-imaging agent. Pimonidazole binds cellular thiols under hypoxic conditions but the spatial resolution of imaging is poor. To improve the imaging resolution, we will develop a fluorogenic hypoxia-activated protecting group that will become fluorescent upon release of the active compound. This will provide a read-out of when and where the active compound is delivered, and fill also find application in the general imaging of hypoxia. We then aim to apply this technology to developing hypoxia-activated inhibitors of the cAMP response element binding protein binding protein (CREBBP) bromodomain. CREBBP is a histone acetyl transferase involved in regulating transcription; it has ~400 interacting protein partners making it a key node in the mammalian protein-protein interactome. One partner is hypoxia-inducible factor-1α (HIF-1α), which is a transcription factor that responds to changes in cellular oxygen levels. Given the large number of CREBBP interacting partners it is preferable to target the CREBBP bromodomain inhibitor using a hypoxia-activated group. In this way it will be possible to ascertain the role of the CREBBP bromodomain in hypoxic tumours.
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