Kevin Cuthbertson MChem AMRSC
Kevin came from a family with a background in marine engineering but decided to deviate from the family trade, pursuing a life in chemistry instead. Originally deciding to study chemistry at Newcastle University in 2011, Kevin soon changes course to chemistry with medicinal chemistry. He was fascinated by the role of organic molecules in biology and medicine and, between his penultimate and final year, began an RSC funded summer placement at the Northern Institute for Cancer Research. Here he worked on the synthesis of PARP inhibitors and did his final year dissertation on inhibitors of DNA-PK. On completing an MChem with Honours in Chemistry and Medicinal Chemistry, Kevin was awarded a first class degree and the Astra Zeneca Hayley Whitfield Prize for achieving the top mark among his peers.
In 2015 Kevin then began studying a PhD in Leeds with Dr Richard Foster and Prof David Beech. Their work is based on ion channel pharmacology for cardiovascular research. Kevin is studying Piezo1, a mechanosensitive ion channel, and is interested in designing and synthesising small molecules to modulate Piezo1 function in cells. This research at the dawn of Piezo1 pharmacology, as there is only one published drug-like compound that interacts with Piezo1.
Piezo1 is a mechanosensitive ion channel involved in numerous cellular functions and disease states.1–7 Discovered in 2010, along with Piezo2, by Patapoutain et al. in an attempt to find mammalian an ion channel involved in mechanotransduction.8 This has revitalised research into mechanotransduction, as little is known about the mechanism of pressure sensing in mammalian cells. Apart from the lack of mammalian channels to study; mechanosensitive ion channels is also difficult to study due to the intricate assays required. This issue was addressed in 2015 with the discovered of Yoda1 (Figure 1), a chemical activator of Piezo1, by the Patapoutain group.9 This allows for Piezo1 to be studied without complex assays involving mechanical stimuli, and gives a starting point novel small molecule modulators.
We have begun work on designing and synthesising analogues of Yoda1 to improve potency, properties and identify small molecules with novel pharmacology. Using two approaches to developing Yoda1 analogues: small modifications to elucidate structure activity relationships (SAR) and large changes in an attempt to scaffold-hop to a novel compound. This has allowed us to build SAR around Yoda1 and discover scaffolds with novel pharmacology. We have also made progress in finding the binding site of Yoda1, using computational methods and site-directed mutagenesis.
(1) Kim, S. E.; Coste, B.; Chadha, A.; Cook, B.; Patapoutian, A. The Role of Drosophila Piezo in Mechanical Nociception. Nature 2012, 483 (7388), 209–212.
(2) Pathak, M. M.; Nourse, J. L.; Tran, T.; Hwe, J.; Arulmoli, J.; Le, D. T. T.; Bernardis, E.; Flanagan, L. A.; Tombola, F. Stretch-Activated Ion Channel Piezo1 Directs Lineage Choice in Human Neural Stem Cells. Proc. Natl. Acad. Sci. U. S. A. 2014, 111 (45), 16148–16153.
(3) Ranade, S. S.; Qiu, Z.; Woo, S.-H.; Hur, S. S.; Murthy, S. E.; Cahalan, S. M.; Xu, J.; Mathur, J.; Bandell, M.; Coste, B.; et al. Piezo1, a Mechanically Activated Ion Channel, Is Required for Vascular Development in Mice. Proc. Natl. Acad. Sci. U. S. A. 2014, 111 (28), 10347–10352.
(4) Cahalan, S. M.; Lukacs, V.; Ranade, S. S.; Chien, S.; Bandell, M.; Patapoutian, A. Piezo1 Links Mechanical Forces to Red Blood Cell Volume. Elife 2015, 4, e07370.
(5) Bae, C.; Gnanasambandam, R.; Nicolai, C.; Sachs, F.; Gottlieb, P. A. Xerocytosis Is Caused by Mutations That Alter the Kinetics of the Mechanosensitive Channel PIEZO1. Proc. Natl. Acad. Sci. 2013, 110 (12), E1162–E1168.
(6) Albuisson, J.; Murthy, S. E.; Bandell, M.; Coste, B.; Louis-Dit-Picard, H.; Mathur, J.; Fénéant-Thibault, M.; Tertian, G.; de Jaureguiberry, J.-P.; Syfuss, P.-Y.; et al. Dehydrated Hereditary Stomatocytosis Linked to Gain-of-Function Mutations in Mechanically Activated PIEZO1 Ion Channels. Nat. Commun. 2013, 4 (May), 1884.
(7) Gudipaty, S. A.; Lindblom, J.; Loftus, P. D.; Redd, M. J.; Edes, K.; Davey, C. F.; Krishnegowda, V.; Rosenblatt, J. Mechanical Stretch Triggers Rapid Epithelial Cell Division through Piezo1. Nature 2017, 543, 118.
(8) Coste, B.; Mathur, J.; Schmidt, M.; Earley, T. J.; Ranade, S.; Petrus, M. J.; Dubin, A. E.; Patapoutian, A. Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels. Science (80-. ). 2010, 330 (6000), 55–60.
(9) Syeda, R.; Xu, J.; Dubin, A. E.; Coste, B.; Mathur, J.; Huynh, T.; Matzen, J.; Lao, J.; Tully, D. C.; Engels, I. H.; et al. Chemical Activation of the Mechanotransduction Channel Piezo1. Elife 2015, 4 (MAY), 1–11.
- MChem with Honours in Chemistry and Medicinal Chemistry
Research groups and institutes
- Chemical Biology and Medicinal Chemistry