Summary of 8th RSC-BMCS / SCI Symposium on Ion Channels as Therapeutic Targets – April 2025
March 31st – 1st April 2025
Hinxton Hall, Wellcome Genome Campus, Cambridge
By Dr Al Dossetter
The SCI/RSC Ion-channels conference covers all aspects of ion-channel research; thus there is a mix of medicinal chemistry / drug discovery, protein bio-science and methodology talks. It is a great meeting to get to know the area and make contacts with experts.
The meeting, originally scheduled for 2 years ago and delayed by the pandemic, really showed how cryo-Em structural determination was making an impact on research in the area, and this year it continues to have a huge impact. In concert with this technology, the molecular biology of single point mutation work has also born much fruit.
Apologies up front for not highlighting any of the posters – the conference was so good for networking that I did not have time to visit! – sorry to everyone that worked hard on them.
Below are some notes from the talks with some added insights / interpretations from MedChemica added.
In order they were presented:
Sven Van Brandt – J&J Innovative Medicine
Identification of Selective GluN2A Negative Allosteric Modulator Tools Suitable for in Vivo Exploration
The candidate drug profile required CNS penetration as the target looked applicable for the treatment of neurodegenerative disorders; tool compounds would be ideal for in-vivo studies. Starting from TCN-201 the team removed the hydrazine group and changed heterocycles (1). The sulphonamide compounds have higher polar surface area and so lead to poor brain penetration. Exploration of the shape showed the compounds folded, due to the sulphonamide yielding the ideal shape, to fit in the binding pocket. Exploring the linker groups yielded a difluoro ether compound (2). The gem-difluoro group gave the compounds the folded shape required for binding. Further shape optimisation with a cyclopropyl group and further heterocycle optimisation gave the final tool compound (JNJ 78911118). The compound has improved brain penetration, solubility, clearance and bio-availability and GluN2A binding of 40 nM.
Looking at our matched pair database we find that sulphones increase efflux ratio. It is reasonable then that this would keep a compound in the periphery.
Change of H to methyl sulphone. MDCK 15 matched pairs – 12 pairs increase ER.
Katie Simmons, University of Leeds
Discovery of Novel KCNT1 Ion Channel Inhibitors for the Treatment of Epilepsy
Inhibition of KCNT1 ion-channel looks an attractive target to treat severe childhood epilepsy. These diseases have very poor prognosis, current drugs and improved diet have limited effects. The team took an approach of working from weak inhibitors (like BC12 and cyroEm structures 5U70) and virtual screening. Of the virtual hits were 9 approved drugs; two were profiled against KCNT1 (WT & Y796H) and one looked very promising. An agreement has been reached to workup this compound and is currently awaiting funding.
Further docking of Zinc20 gave 73 compounds and, with a lead compound from Praxis, gave good chemical start points. The group are using MCPairs to help improve compound properties.
BC12 and the Praxis Compound
Stephen Tucker, University of Oxford
CryoEM Structure of the THIK-1 (KCNK13) K2P Potassium Channel
In Stephen’s talk we learned about K2P type of potassium channels which have a different architecture and gating to “classical K+ channels”. The structures can be considered as a dimer of dimers. Stephen described the extracellular portion of the molecule as having an ‘interesting hat’. The top of the four proteins come together and thus the channel does not have a straight-line channel for the metal ions to pass through – imagine a curve and the ions emerging at an angle.
Twik-Related-Halothane-inhibited K+ (THIK) channel is GPCR regulated at the cell surface of microglia. Stephen described from cyro-em structures the mechanism for key tyrosines and how the shape changes to allow the passage of ions. A structure was presented of linoleic acid binding and activating the channel. As the name of the channel suggests they are activated by halothanes (part of their discovery?).
Louisa Zolkiewski, ApconiX
Benefits of early in vitro screening for seizure liability in problem solving and decision making
Lousia described ApconiX in-vitro seizure liability assay system (iSLA). Seizure is the sudden, uncontrolled electrical disturbance in the brain. The assay system consists of multiple panels of assays consisting of several ion-channels that can be run quickly and in advance of most complex lower throughput assays like Zebra fish larva locomotion, Rodent hippocampel slice assay and observational / EEG rodent studies.
The ion-channels are Kv1.1, Kv2.1, Kv3.1, Kv4.2(4.3), Kv7.2(7.3), Kv7.3(7.5), KCa1.1, KCa4.1, Nav1.1, Nav1.2, Nav1.6, GABAa1/b2/y2, Nicotino a4b2, NMDA 1/2A.
Using SAR from data from three of these (Nav1.2, Kv1.2, GABA) compounds were selected for further screening to understand the panel and identify the features in compounds frequently seen in the inhibitor / modulators. Good results were obtained leading to good predictivity of known seizure compounds and clean compounds.
Contact ApconiX for further details of iSLA screening service for your project.
MedChemica regression forest Machine Learning (ML) models use “pharmacophore” dyads to describe molecules. These are two chemical features separated by a linker. Bupropion was one of the compounds selected for study. Below is output predictions from MedChemica’s MCPairs for 5-HT2a binding. The first feature dyad depicted is HD_5atom_Hal – [Hydrogen Donor – 5 atom linker – Halogen]. Compounds with this feature tend to be potent binders. The prediction is the sum of the contributions from features. In the manner below MCPairs shows how the ML model has made the prediction and more importantly the key chemical features involved.
Alison Obergrussberger, Nanion Technologies
Emerging electrophysiological tools for studying lysosomal ion channels and transporters as drug targets
Apologies I missed this talk as I had a call to take!
Daniel Mihaylov, MRC Laboratory of Molecular Biology
The wide wild world of human GABAA receptors
GABAs are mediators of rapid inhibitory synaptic transmission in the nervous system of vertebrates, and are involved in epilepsy, insomnia and anxiety. There are 19 human GABA genes. Each ion-channel consists of 5 subunits (mixture of a, b and g). Using time resolved cyro-EM it is possible to “see” the states of the receptor, and opening and closing of the channel. Daniel showed some of the learnings from this work.
Paul Miller, University of Cambridge
Molecular mechanisms of action of antibodies against GABAA receptors that modulate anxiety
Paul’s team raised nano-bodies to interact with sub-units of GABA receptor channels and studied the effects. Selectivity between sub-types in GABA needs to be efficacy based and not to be judged on binding affinity of the nanobodies, was a key learning of the work.
Trevor Wilkinson, Astrazeneca
Modulating Ion Channel Function with Biologics: Opportunities and Challenges
Mono-clonal antibodies have not been explored for ion-channel inhibition / modulation. The process of raising Mab use Humanised Mice or alternate hosts like Llama or chicken. The team generated Mabs for Kv1.3 (see PDB 7SSZ with Mab attached). P2X4 was studied and 10 inhibitory Mab found of these, one was found to be a full inhibitor.
Sara Bonvini, Astrazeneca
The therapeutic potential of ion channels in cough: what could the future hold?
Surprisingly 9.6% of adults have a chronic cough (in western countries where data was collected). These patients account for a significant number of visits to the doctor and follow up care without any improvement. Cough is a defensive mechanism and several ion-channels in the lung linked to vagus nerve are thought to be involved. Molecular biology enables the generation of humanised animal models for study (count the coughs).
High ATP in patients and some good evidence to inhibit ATP receptors. P2X3 and dual (P2X2/3) compounds have been trialled and used [Gefapixant and Camlipixant McGarvey et al Lancet 2022, 399, 909].
TRPV1 appears to be activated at higher temperature (>43oC). A clinical trial got target engagement but no objective effect on Cough
TRPA1 – low temperature (<10oC) and smoking. Ph II study ongoing with GDC-6599
TRPM8 – middle temperature 10 – 25oC – Ph II study with AX-8 and agonist.
TRPV4 – middle/high temperature 27 – 34oC and wet. GSK2793874 assessed in Ph IIb – lack of efficacy.
Nav1.7 – throat spray with lidocaine. Taplucainium [NTX-1175] (Nocion Therapeutics) in Ph IIb [https://www.businesswire.com/news/home/20240715222816/en/Nocion-Therapeutics-Presents-Data-on-Preclinical-and-Clinical-Development-of-Taplucainium-a-Novel-Charged-Sodium-Channel-Blocker-as-a-potential-treatment-for-Chronic-Cough-at-the-13th-London-International-Cough-Symposium]
Research has shown that cough is more prevalent in women than men – no understanding of why.
Anna Moroni, University of Milan
Towards subtype-specific treatment of HCN channel dysfunctions
HCN4 is linked to bradycardia / tachycardia
HCN1 is linked to early infancy epilepsy.
Anna described some of their work on HCN4 with cyro-EM to understand the channel, mechanisms and binding sites. Extensive single point mutations were found by studying patients with disease – excellent work (too much to write down). Work was also described with nanobody modulators, this should that extracellular modulation was possible.
Thomas Voets, KU Leuven
TRPM3 as a therapeutic target for pain and neurological diseases, from structure-function analyses to animal models and drug development
Thomas gave his talk virtually from the USA.
TRPM3 – an ionotropic steroid receptor that is highly expressed in the brain. KO mice are healthy and immune to certain pain models.
TRPV1 / TRPM8 – modulate the thermoregulatory process – care must be taken to be selective with any designed drug.
The discovery phase yielded a compound BHV2100 that is described in a patent with this Markush:
The compound was designed to be periphery only.
The team learnt from the outcome of AMG-512 dosed at 10mg/Kg that it caused body temperature rises. BHV2100 causes no such effects and was tested at 1000mg/Kg for 8 days (presumably rodent?)
In Ph1 a good rise in blood levels which were dose dependant (25 to 500 mg). The compound is currently in Ph II for acute migraine.
Daniel Basting Bayer AG
Restoring autonomic balance in Heart Failure (HF) patients via positive allosteric M2 modulators (PAM) acting on the M2 GIRK1/4 channel axis.
It has been known for some time that the M2 receptor can control the GIRK1/4 ion channels. The team were looking for a PAM compound for the M2 receptor to give the desired action on the ion-channel in HF patients.
An HTS of 3.16 million compounds (using a coupling Ca2+ assay readout) yielded 1373 hits of which 888 were confirmed. Further triage led to 31 compounds of which 29 were chinolones and 2 singletons. The hits did not have selectivity over M1 or M4.
The route described in the figure below shows a couple of key compounds on the way to the 8nM PAM candidate drug. Using a xtal structure (4MQT) the team modelled the compound and believe they understand the binding mode. The route to the compound is a 5 step + 3 step convergent synthesis. Publication JMC, 2024, 67, 19165
Figure – Optimisation of the hit compound to BAY 2413555
In vivo work showed a reduction in heart rate with blood pressure effects in rat. Good telemetric data in dog and pig.
In Ph 1 – a dose dependant reduction in heart rate was observer but longer term adverse effects were found and the compound stopped.
Christopher Johnson, Astex
Enabling High Throughput Electron Cryo-microscopy for Structure-based Design
Astex routinely use Cyro-EM for structure determination. They invested a few years ago in the machinery but more importantly, standardising the process for consistent reproducibility. Data management was just as important to process. The cycle time is 1 week from the point of request. Chris described work on the target TRPML1, walking through many structures and compounds describing the ligand binding site.
Henry Danahay, Enterprise Therapeutics
ETD001: the last in class but best in class inhaled ENaC blocker?
The team at Enterprise TX were aiming to discover and develop an inhibitor of ENaC for the treatment of Cystic fibrosis. The compound ENT-001 is currently in Ph II clinical trials and will read out this year. ENaC is a voltage gated 4Ps sodium channel and controls fluid (mucus gel) in the lung. In the disease state Na+ is sucked in but chloride is not pumped to maintain a balance, thus a build-up of mucus which can lead to infection. Several compounds have entered the clinic (with compounds blocking the channel) and have shown to be effective. However,dosing is limited due to compound entering the systemic circulation and causing toxic side effects.
Initially, the compounds had a similar war-head group and varying side chains, most of which were added to stop penetration through the lung. The team changed the heterocycle war-head and experimented in different extended side chains. This combination of groups led to the lead compound which does not reach the kidney and thus does not have the side-effects. After dosing, target Cmax in an hour,which is potentially beneficial in avoiding a ‘spike’ concentration on initial dosing.
An analysis was presented from PK/PD work that suggested previous ENaC compounds were under-dosed to patients.
ETD-001 – I think I wrote down the structure correctly.
And finally….
Poster prize was won by Chris Auberger. The people poster prize was Kasia Hammond. The exhibition passport prize was won by Giuseppe Nano