Development of small molecule inhibitors of the Orai1 channel as potential therapeutics for cardiovascular diseases

Ca2+ is involved in a wide range of cellular processes including signalling, mitochondrial regulation, motility and apoptosis. Orai1 is the pore-forming protein subunit of the calcium-release activated calcium (CRAC) channel, which was identified in 2006. This is a highly Ca2+-selective plasma membrane channel which refills the endoplasmic reticulum stores after depletion caused by a signalling event. This is known as store-operated calcium entry (SOCE) and is the main source of Ca2+ influx into non-excitable cells. Orai1 has been subject to considerable research regarding its structure, mode of action and clinical relevance. It plays a vital role in the mammalian immune system and has been proposed as a drug target in the areas of immunology, inflammatory disease and cancer, with other indications still emerging.

Unpublished research from the University of Leeds links Orai1 upregulation to pathological vascular smooth muscle cell remodelling, with the potential to target it as a therapeutic strategy. A novel series of Orai1 inhibitors was developed, with the lead compound being potent, selective and effective in vitro and in vivo. This PhD project expands upon this series of Orai1 inhibitors to improve potency and to better understand the structure-activity relationship of the compounds. Synthetic organic chemistry and computational methods are being used together to design and make structurally distinct compounds to improve upon ADME properties towards a more clinically suitable molecule. Literature Orai1 inhibitors have also been synthesised with the intent to develop chemical probes, which could be used for binding site elucidation and in biodistribution and imaging studies.