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Synthesis and biological evaluation of novel potassium channel inhibitors for the development of treatments for KCNT1-related epilepsy

   Faculty of Biological Sciences

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  Dr Katie Simmons, Dr Martin McPhillie, Dr S Muench, Dr J D Lippiat  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

Inherited variations in the KCNT1 ion channel cause severe childhood epilepsy, with frequent seizures, intellectual and motor disabilities. These rare forms of epilepsy cannot be controlled by any presently-available medicine, though the use of quinidine has been trialled. Quinidine therapy reduced seizures in a small minority of cases. Unfortunately, quinidine is even better at altering the heartbeat, which can be fatal and limits its use.

We have recently identified novel inhibitors using computer-aided ligand-discovery that are more potent than quinidine. This project aims to develop synthetic routes to these compounds and synthesise analogues to probe the structure-activity relationships of these inhibitors. Synthesised molecules will then be tested using well established cell-based assays.

The project will combine medicinal chemistry and molecular biology approaches to develop and test putative new therapeutics to treat epilepsy. The student will perform both synthetic chemistry and cell-based assays, and therefore gain a wide range of transferable skills including organic chemistry, molecular biology, in silico ligand design, cell-based assays and in vitro pharmacokinetic evaluation.


Applicants should have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. A Masters degree is desirable but not essential.

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.0 overall with at least 5.5 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid. Some schools and faculties have a higher requirement.

How to apply

To apply for this scholarship opportunity applicants should complete an online application form and attach the following documentation to support their application. 

  • a full academic CV
  • degree certificate and transcripts of marks
  • Evidence that you meet the University's minimum English language requirements (if applicable)

To help us identify that you are applying for this scholarship project please ensure you provide the following information on your application form;

  • Select PhD in Biological Sciences as your programme of study
  • Give the full project title and name the supervisors listed in this advert
  • For source of funding please state you are applying for an advertised Faculty Scholarship

As an international research-intensive university, we welcome students from all walks of life and from across the world. We foster an inclusive environment where all can flourish and prosper, and we are proud of our strong commitment to student education. Within the Faculty of Biological Sciences we are dedicated to diversifying our community and we welcome the unique contributions that individuals can bring, and particularly encourage applications from, but not limited to Black, Asian, people who belong to a minority ethnic community, people who identify as LGBT+; and people with disabilities. Applicants will always be selected based on merit and ability. 

For further information about this scholarship please contact the Faculty Admissions Team

e: [Email Address Removed]

Funding Notes

This scholarship will attract an annual tax-free stipend of £17,668 (2022/23 rate) for up to 3.5 years, subject to satisfactory academic progress. The award will also cover the academic fees at the UK fee rate. Due to limited funding we can only consider applicants for this position who are eligible to pay academic fees at the UK fee rate.


1. Orritt KM, Newell JF, Germe T, Abbott LR, Jackson HL, Bury BKL, Maxwell A, McPhillie MJ*, Fishwick CWG. De Novo Design of Type II Topoisomerase Inhibitors as Potential Antimicrobial Agents Targeting a Novel Binding Region, RSC Medicinal Chemistry, 2022, doi:/10.1039/D2MD00049K
2. Dokla EME, Abdel-Aziz AK, Milik SN, McPhillie MJ, Minucci S, Abouzid KAM. Discovery of a Benzimidazole-based Dual FLT3/TrKA Inhibitor Targeting Acute Myeloid Leukemia. Bioorganic & Medicinal Chemistry, 2022, 56. doi: /10.1016/j.bmc.2021.116596.
3. Simmons KJ, Wilkinson CG, Viswambharan H, Haywood NJ, Bridge KI, Turvey SJ, Armstrong T, Lunn L, Meakin PJ, Clavane E, Beech DJ, Cubbon RM, Wheatcroft SB, McPhillie MJ, Fishwick CWG, Kearney MT. A small molecule reveals role of insulin receptor-insulin like growth factor-1 receptor heterodimers bioRxiv
4. Cole BA, Johnson RM, Dejakaisaya H, Pilati N, Fishwick CWG, Muench SP, Lippiat JD. Structure-Based Identification and Characterization of Inhibitors of the Epilepsy-Associated KNa1.1 (KCNT1) Potassium Channel. iScience. 2020 May 22;23(5):101100. doi: 10.1016/j.isci.2020.101100
5. Caseley EA, Muench SP, Baldwin SA, Simmons KJ, Fishwick CW, Jiang L-H. Docking of competitive inhibitors to the P2X7 receptor family reveals key differences responsible for changes in response between rat and human. Bioorg. Med. Chem. Letts.  2015. 25(16), pp. 3164-3167 
6. Lolicato, M. Bucchi, A. Arrigoni, C. Zucca, S. Nardini, M. Schroeder, I. Simmons, K.J. Aquila, M. Di Francesco, D. Bolognesi, M. Schwed, F. Dmitri, K. Fishwick, C.W.G. Johnson, A.P. Thiel, G. A binding pocket for cyclic dinucleotides in the C-linker of HCN4 allosterically controls the response of the channel to cAMP. Nat. Chem. Biol. 2014, 10, pp. 457-462.
7. Simmons, K.J*. Gotfryd, K. Billesbølle, C.B. Loland, C.J. Gether, U. Fishwick, C.W.G. Johnson, A.P. A Virtual High-throughput Screening Approach to the Discovery of Novel Inhibitors of the Bacterial Leucine Transporter, LeuT. Mol. Membr. Biol. 2013, 30, pp. 184–194.
8. Wacker, S.J. Jurkowski, W. Simmons, K.J. Fishwick, C.W.G. Johnson, A.P. Madge, D. Lindahl, E. Rolland, J.F. de Groot, B.L. Identification of Selective Inhibitors of the Potassium Channel Kv1.1-1.2(3) by High-Throughput Virtual Screening and Automated Patch Clamp. ChemMedChem. 2012, 7, pp. 1775-1783.

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