A Novel K+ Channel Target (KCNK13/THIK1) for Neurodegenerative Disorders: Understanding its mechanism of inhibition by small molecule drugs and biological therapeutics
LEAD SUPERVISOR: Prof. Stephen Tucker, Kavli Institute for Nanoscience Discovery, Department of Physics (CMP)
Co-supervisor: Prof. Simon Newstead, Kavli Institute for Nanoscience Discovery, Department of Biochemistry
Commercial partner: Cerevance
The student will be involved in an exciting multidisciplinary project aimed at determining the structural and molecular mechanisms of a range of novel inhibitors of the THIK1 K2P K+ channel. These drugs have been developed by our industrial partner, Cerevance (Cambridge, UK) for the treatment of neurodegenerative disorders such as Alzheimers Disease and Amyotrophic Lateral Sclerosis (ALS).
The inhibition of THIK1 channels in microglia prevents the release of inflammatory mediators and dampens the maladaptive central neuroinflammation often associated with these disorders. Importantly, this has been shown to delay the progression of neurodegenerative disease in animal models, and Cerevance will begin Phase 1 clinical trials of a potent, highly-selective THIK1 inhibitor (CVN292) in Q4 2023.
However, despite the fact that many related K2P channel structures are known, no structural data currently exists for THIK1. Its binding site for CVN293 and the mechanism by which this drug inhibits channel activity therefore remain completely unknown.
The host lab has extensive experience in dissecting the structure/function relationship of K2P K+ channels as well understanding their mechanism of pharmacological regulation (Dong, Science 2012; Schewe, Cell 2017, Science 2019; Rödström, Nature 2020; Sörmann, Nature Genetics, 2022). Similar approaches, including Cryo Electron Microscopy, will therefore be used in combination with a range of other cutting-edge biophysical, computational and electrophysiological approaches to determine the binding site for these drugs and study their regulation of THIK1 channel activity.
In collaboration with Cerevance this information will be used to understand the selective inhibition of THIK1 channels in microglia and will also be used to investigate the development of novel biological therapeutics that target THIK1. The project will be co-supervised by Prof Simon Newstead (Dept Biochemistry) and will be based in the Kavli Institute for Nanoscience Discovery next to the Dept Biochemistry. Combined with the skills/training available through this PhD program this project offers the student an unparalleled choice of multidisciplinary training in cutting-edge technologies in a world-class biomedical research environment.
Apply using course: DPhil in Condensed Matter Physics
