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ION CHANNEL TARGETS unlocking the potential

A striking number of targeting ion channels have reached blockbuster status, generating $ billion revenues. In spite of the historical success of ion channels as therapeutic targets and the considerable investment in this target class by the industry, not a single novel, small molecule ion channel drug has been approved by the FDA in the past 10 years.This article will provide an overview of the current status of ion channel drug discovery and the technologies currently available to the industry for undertaking ion channel R&D programmes. In addition, this review will highlight emerging discovery approaches to this valuable target class that may initiate a paradigm shift in ion channel drug discovery.

espite billions of dollars of research spend, channels as therapeutic targets. Indeed 400+ ion By Dr Dayle S. Hogg, the pharmaceuticals industry has been channel have been identified. The potential Dr Philip Boden, Dunable to replicate the early success of com- validation of these as drug targets provides an Dr Geoff Lawton pounds such as the antagonists, sulphony- enormous market opportunity for the re-emer- and Dr Roland Z. lureas and local anaesthetics. Indeed, since the gence of ion channels as key targets in drug dis- Kozlowski approval of Posicor () in 1997, and its sub- covery. However, to realise the potential of this tar- sequent withdrawal, a paucity of ion channel thera- get class, an understanding of the validation of peutics have been approved by the US Food and these targets as well as development of suitable Drug Administration (FDA). Despite this poor suc- screening technologies that reflect the complexity cess the pharmaceutical industry continues to invest of ion channel structure and function remain key vast resources in ion channel research. This research drivers for exploitation of this opportunity. targets many different therapeutic indications with a combined market value of more than $24 billion and Ion channel therapeutics also provides a key filter in safety . In A history of success addition to the fully integrated pharmaceutical com- Historically, drugs targeting ion channels have panies, a number of biotechnology companies are been well represented as important therapeutics also active in this field (see Table 1). for a number of key indications including cardio- In light of the significant historical success of ion vascular disorders such as angina, hypertension channel therapeutics, that were largely identified and cardiac ; metabolic disorders such prior to the genomic bubble of the early 1990s, the as type II diabetes; and neurological disorders global scientific community has generated huge such as and stroke; in addition to their use as quantities of biological data in relation to ion local anaesthetics.

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Table 1: Ion channel focused biotechnology companies

COMPANY LOCATION WEBSITE

Cardiome Pharma Corp Vancouver, BC, Canada www.cardiome.com

Icagen, Inc Durham, NC, USA www.icagen.com

Lectus Therapeutics Ltd Cambridge, UK www.lectustherapeutics.com

Neurion Pharmaceuticals, Inc Pasadena, CA, USA www.neurionpharma.com

NeuroMed Pharmaceuticals, Inc Vancouver, BC, Canada www.neuronmed.com

NeuroSearch A/S Ballerup, Denmark www.neurosearch.com

Newron Pharmaceuticals SpA Milan, Italy www.newron.com

Xention Discovery Ltd Cambridge, UK www.xention.com

A number of these ion channel drugs have treatment of partial , primary and second- reached blockbuster status such as Pfizer’s calcium ary tonic-clonic seizures, and seizures associated Norvasc® ( besylate). with Lennox-Gastaut syndrome. Indeed, the L-type as a target for An ion channel blocker with an entirely novel antihypertensive and/or anti-anginal therapies has mode of action, Pfizer’s Neurontin® (), been the subject of intense interest which is direct- was approved by the FDA in 1993 for adjunctive ly reflected in the number of calcium channel therapy in the treatment of partial seizures in antagonists that have been approved by the FDA. adults and paediatric patients. Gabapentin is a These can be broadly divided into three distinct compound that was originally designed as a GABA classes: the dihydropyridine calcium channel mimetic, however, it has since been shown that blockers (eg, Plendil®, AstraZeneca; Norvasc®, gabapentin may exert its efficacy through a novel Pfizer; and Adalat®, Bayer), the phenylalkylamine mechanism of action; through binding to an acces- calcium channel blockers (eg, Calan®, Pfizer; sory of a calcium channel (see below for Verelan®, Elan) and the benzothiazepine calcium further details). Gabapentin has also more recently channel blockers (eg, Cardizem®, Aventis/Biovail; (2002) been approved for pain management of Tiazac®, Forest Laboratories). Calcium channel postherpetic neuralgia in adults. However, off- antagonists still form a significant proportion of label use of gabapentin for indications such as the global cardiovascular market and as a target panic disorder, prophylaxis, social pho- class, despite the expiry of key patents currently bia, mania, bipolar disorder and with- generate ~$6.5 billion in annual sales. drawal may have also significantly contributed to Anti-epileptic drugs (AEDs) also include a signif- the commercial success of this drug1-3. icant number of blockers of ion channels In addition to L-type calcium channels and volt- such as Novartis’ Tegretol® () indi- age-gated sodium channels, ATP-regulated potassi- cated for control of partial seizures. The 1990s saw um channels have also received focus as key ion the introduction of newer ion channel AEDs such channel therapeutic targets for the treatment of as Ortho-McNeil Pharmaceuticals’ Topamax® type II diabetes4. The sulphonylurea (), a blocker which channel blockers exemplify this success. These received FDA approval in 1997 as an adjunctive include Aventis’s Amaryl® (), which therapy for control of partial onset seizures. More binds to sulphonylurea -1. This receptor recently in 2005, Topamax® also received FDA forms a multimeric complex with the Kir6.2 potas- approval as initial monotherapy in people aged sium channel on pancreatic beta cells that regulate >10 with partial onset or primary generalised release. tonic-clonic seizures. (marketed as -activated anion channels such as the Lamictal® by GlaxoSmithKline) a different sodi- GABAA-receptor channel complex have um channel blocker, is also currently used in the also been successfully targeted for the treatment of

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Insomnia. In 1999, Wyeth received approval of made an initial payment of $25 million to Sonata® (zaleplon), for short-term treatment (7-10 Neuromed and will pay an additional $450 mil- days) of insomnia in adults. lion in milestone payments based on the success of Thus, the pharmaceutical industry has success- its experimental products for pain and other neu- fully developed a wealth of therapeutics targeted at rological disorders. Thus considerable commercial selected calcium, potassium, sodium and chloride opportunities exist for the novel modulators of ion channel targets. Given the number of genes identi- channels in areas of unmet medical need. fied in the human genome project it would appear In a further significant advancement in ion chan- that there remains a significant pool of unexploit- nel drug discovery, FDA approval has also been ed space within the ion channel field for this clear- given for the first therapeutic use of a selective ly pharmacologically tractable target class. activator (non-ligand gated chlo- ride channel). Anionic channels, which appear rel- Recent developments atively underexploited compared with their cation- Given the historical success of targeting ion chan- ic channel counterparts are emerging as key thera- nels in drug discovery, the development of new peutic targets as their role in physiological and screening technologies and a greater understanding pathophysiological functions advances5. In early of the genetics, structure and function of ion chan- 2006, Sucampo Pharmaceuticals, Inc announced nels, expectations of ion channel drugs have that the FDA had approved the new drug applica- remained high. It is therefore interesting to note tion for AMITIZA™ (lubiprostone), a CLC-2 that since 1997, the number of entirely ion channel chloride channel activator capsules, for chronic drugs approved by the FDA has been limited. idiopathic constipation in adults. However, in this period, discounting new formula- An example of an ion channel drug which exerts tion and incremental improvements to existing its effects through a novel mechanism of action therapies, there have been a few notable develop- (through binding to ion channel accessory ) ments that expand the diversity of clinically vali- Pfizer’s Neurontin® (gabapentin), lost its product dated therapeutic ion channel targets. exclusivity in mid-2005. Consequently, Pfizer intro- Recent approvals include Prialt® () duced Lyrica® (), an analogue of from Elan Corporation in 2004. Prialt® is a syn- gabapentin, which gained FDA approval in late 2004 thetic equivalent of a naturally occurring for use in associated with diabetic conopeptide found in a marine snail known as and postherpetic neuralgia; Conus magus, which selectively blocks N-type cal- making it the first FDA-approved treatment for both cium channels on sensory neurones. This drug is of these neuropathic pain states and further exempli- administered intrathecally via a surgically fying the role of calcium channels as important ther- implanted catheter, and is indicated for the man- apeutic targets in neuropathic pain states. agement of severe chronic pain in patients for Additional recent developments have also seen whom intrathecal therapy is warranted, and who Novartis receive FDA approval in 2001 for its oral are intolerant of or refractory to other treatment, therapeutic agent Starlix® () for the such as systemic analgesics, adjunctive therapies management of type II diabetes. Nateglinide is a or intratheal morphine. Prialt® represents devel- non-sulphonylurea ATP-regulated potassium chan- opment of the first clinically approved N-type cal- nel blocker. cium channel blocker and provides a clinical Noticeably, since 2000, only Prialt® and exemplification of a new mechanistic approach Amitiza™ address ‘new’ ion channel targets indi- for this target for the treatment of serve pain syn- cating perhaps an underlying difficulty in progress- dromes. However, given the limitations afforded ing ion channel modulators though development by a peptide-based drug and intrathecal adminis- and on to the market and also highlighting a void tration, significant opportunities for the next-gen- of new ion channel drugs. eration of orally available small molecule N-type calcium channel blockers exist. Indeed these Ion channel discovery opportunities can be can be further exemplified by Multimeric ion channel complexes as the recent research and in-licensing deal signed therapeutic targets between Neuromed, Inc and Merck which Ion channels are a complex scaffold of multimeric includes Neuromed’s drug candidate, proteins which display differential cellular and tis- NMED-160, an N-type sue specific expression patterns. The core mem- which is in midstage testing for chronic pain. brane spanning domains of ion channels form the Under the terms of the agreement, Merck has channel ‘pore’. These pore-forming domains

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References Table 2: Key high-throughput providers 1 Mathew, NT, Rapoport,A, Saper, J, Magnus, L, Klapper, J, INSTRUMENT SUPPLIER WEBSITE Ramadan, N, Stacey, B and Tepper, S. Efficacy of CytoPatch™ Automat Cytocentrics AG www.cytocentrics.com gabapentin in migraine prophylaxis. Headache, 41, 119- Dynaflow 16 Cellectricon AB www.cellectricon.com 28, (2001). 2 Chouinard, G.The search for new off-label indications for Flyscreen® 8500 Flyion GmbH www.flyion.com antidepressant, antianxiety, antipsychotic and Ion Works® HT Molecular Devices Corp www.moleculardevices.com drugs. J Psychiatry Neurosci., 31, 168- IonWorks® Quattro™ Molecular Devices Corp www.moleculardevices.com 176, (2006). 3 Hamer,AM, Haxby, DG, OpusExpress® 6000A Molecular Devices Corp www.moleculardevices.com McFarland, BH and Ketchum, K. Gabapentin use in a PatchExpress® 7000A Molecular Devices Corp www.moleculardevices.com managed medicaid population. J. Manag. Care Pharm., 8, 266- NPC-1 Port-a-Patch Nanion Technologies GmbH www.nanion.de 71, (2002). 4 Proks, P and Lippiat, JD. Membrane ion channels and QPatch 16 Sophion Bioscience A/S www.sophion.dk diabetes. Curr. Pharm. Des., 12, 485-501, (2006). 5 Kozlowski RZ (Ed): Chloride channels. Publ: ISIS Medical (PFDs) control the flow of sodium, calcium, potas- throughput electrophysiology systems are sum- Media, Oxford (1999). sium or chloride in response to a number of marised in Table 2. Nanion Technologies GmbH 6 Birch, PJ, Dekker, LV, James, IF, Southan,A, Cronk, D. stimuli such as voltage, ligand binding and pH has successfully established its entry level device for Strategies to identify ion which subsequently regulate the conformational automated , the NPC©-1 port-a-patch©, channel modulators: current state of ion channels (eg, open state, closed state and is now launching its second generation instru- and novel approaches to target and inactivated state)6. mentation, the NPC©-16 patchliner©. The patchlin- neuropathic pain. Drug Discov. Ion channel screening er© is a robotic multi-channel patch clamp worksta- Today., 9, 410-8, (2004). 7 Xu, J,Wang, X, Ensign, B, Li, Electrophysiology is the ‘gold standard’ methodol- tion for high quality cellular electrophysiology with M,Wu, L, Guia,A and Xu J. Ion- ogy for ion channels research, which allows increased throughput capabilities. Nanion claims channel assay technologies: detailed kinetic and pharmacological analysis of good success with gigaseal formation (60-80%). quo vadis? Drug Discov.Today., potential drug molecules in real time. This infor- Molecular Devices Corp has incorporated popula- 6, 1278-1287, (2001). mation is of critical importance in attempts to opti- tion patch clamp technology™ in its IonWorks® 8 Townsend,C. Population patch-clamp: an enabling mise compounds as they progress though the hit to Quattro™. This uses multiple recording sites within technology for the discovery lead stages of a drug discovery programme. each well to improve success rate and thus reduce of openers. However, the key limitation of classical resource- the need for sampling in quadruplicate which was a 2006 Automated intensive electrophysiology is throughput. To requirement for its original IonWorks® HT. Seal Electrophysiology Users address these limitations, a number of high- resistances are still only in the order of a hundred Meeting, Salt Lake City (2006). 9 Yu, FH and Catterall,WA. throughput assays have been developed for ion megaohm at best, however, and one group from Overview of the voltage-gated channel screening. These include radioactive flux Glaxosmithkline reported that the seal resistance sodium channel family. assays and also non-radioactive flux assays such as using population patch clamp technology™ was Genome Biol., 4, 207, (2003). atomic absorption spectroscopy, fluorescence actually worse than that for the single hole system in 10 Hockerman, GH, Johnson, assays and colorimetric assays. This area has been its studies of KCNQ2/3 activators8. The technology BD,Abbott, MR, Scheuer,T and 6,7 Catterall,WA. Molecular reviewed recently and provides key tools for clearly is now able to provide a greater degree of determinants of high affinity screening large compound collections in hit identi- quantification and reproducibility than with the - phenylalkylamine block of L- fication programmes. However, such methodolo- lier high-throughput electrophysiology systems but type calcium channels. J. Biol. gies possess some limitations associated with phys- it is still the case that the methodology is best suited Chem., 270, 22119-22122, iological correlation and temporal resolution6,7 at present to screening strategies based around (1995). 11 Levitan, IB. Signaling protein which are central to driving medicinal chemistry cloned ion channel targets expressed in lines complexes associated with programmes though the hit to lead process. rather than study of native cell systems. neuronal ion channels. Nat. More recently, advances in high-throughput elec- Given the limitations of these systems for use Neurosci., 9, 305-10, (2006). trophysiological techniques have been introduced with native cells, compared with cell-lines or which go some way to circumventing these prob- cloned ion channels expressed in cell systems, the Continued on page 89 lems. Key providers of currently available high- issues of physiological relevance need to be clearly

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understood. Cloning efforts have identified a channel and this is achieved predominantly by reg- Continued from page 86 diverse range of ion channels with further diversity ulation of either the kinetics of the current or the being apparent as a consequence of alternative chaperoning of pore-forming subunits to the cell 12 Catterall,WA. Structure 11 and regulation of voltage-gated spicing of products and/or heteromeric assem- membrane . To illustrate this further, two exam- Ca2+ channels.Annu. Rev. Cell bly. Such genetic variation occurs both with the ples will be considered. Dev. Biol., 16, 521-55, (2000). principal pore-forming subunits and their accesso- 13 Dolphin,AC. Beta subunits ry proteins. Despite this diversity, it has been pos- Calcium channels of voltage-gated calcium sible to use molecular correlates of native channels Voltage-activated calcium channels are modulated channels. J. Bioenerg. Biomembr., 35, 599-620, to identify compounds that bind to the pore-form- by a number of accessory proteins which include (2003). 12 ing domains of ion channels. Compounds identi- the ␣2, ␤, ␥, and ␦ subunits . Cav␤ subunits mod- 14 Canti, C, Davies,A and fied using such models have been shown to retain ulate the biophysical characteristics of Cav cur- Dolphin,AC. Calcium Channel predictable activity in native tissues and, as such, rents13. The Cav␤ subunits of voltage-dependent ␣2␦Subunits: Structure, high-throughput screening utilising these technolo- calcium channels also play an important role in Functions and Target Site for ␣ Drugs. Current gies offers a significant opportunity. However, to controlling the surface expression of 1 subunits in . 1, 209- identify compounds that interact at modulatory mammalian cells by binding to a site known as the 217 (2003). sites of ion channels, or their accessory proteins, an alpha interaction domain (AID) present in the intra- 15 Gee, NS, Brown, JP, enhanced temporal resolution of channel kinetics cellular linker between domains I and II of the ␣1 Dissanayake,VU, Offord, J, and a good understanding of their molecular phys- subunits13. Interestingly, trafficking of Cav␣1 sub- Thurlow, R and Woodruff, GN. The novel anticonvulsant drug, ␣ ␦ 14 iology in native tissues is required. The develop- units is also under the control of the 2 subunit gabapentin (Neurontin), binds ment of new screening strategies for the identifica- and this appears to be the binding site for Pfizer’s to the alpha2delta subunit of a tion of ion channel modulators therefore requires Neurontin® (gabapentin)15. calcium channel. J. Biol. Chem., development of a strategy for understanding the Gabapentin was originally designed as a GABA 271, 5768-76, (1996). selectivity of potential ion channel drugs across mimetic and found to be useful as an adjunct for par- 16 Rice,AS and Maton, S. Gabapentin in postherpetic related target channels. This strategy must encap- tial seizures. It has now been shown to have efficacy neuralgia: a randomised, double sulate (i) an understanding of the mode of com- in a wide range of disease states including posther- blind, placebo controlled study. pound binding to ion channels (open state, closed petic neuralgia16 and painful diabetic neuropathy17. Pain, 94, 215-24, (2001). state, inactivated state); and (ii) an understanding Four members of the ␣2␦ subunit have been identi- 17 Rowbotham, M, Harden, N, of the physiological correlation between the com- fied so far and gabapentin binds with the highest Stacey, B, Berntein, P and Magnus-Miller, L. Gabapentin ␣ ␦ 18 position of ion channel protein-complexes and affinity to the 2 -1 subunit . This subunit is also for the treatment of their cytoplasmic signalling pathways in the up-regulated in gabapentin-sensitive animal models postherpetic neuralgia: a desired target tissue. of neuropathy19. randomized controlled trial. Such factors are particularly important to Given the important roles accessory proteins JAMA, 280, 1837-42, (1998). achieve channel-specific or sub-type selective mod- play in regulating ion channel function, Lectus 18 Marais, E, Klugbauer, N and Hofmann, F. Calcium channel ulators when working with ion channels that pos- Therapeutics Limited (Lectus) has developed a pro- alpha(2)delta subunits- sess a high degree of between pore- teomics-based approach to identifying ion channel structure and Gabapentin forming domains. The homologous nature of pore- modulators that exhibits its pharmacological binding. Mol.Pharmacol., forming domains of ion channels9 – the region effects through such proteins. Lectus uses its LEP- 59,1243-8, (2001). which retains the binding site for many ion chan- TICS® technology to immobilise folded, function- 19 Li, CY, Song,YH, Higuera, ES 10 and Luo, ZD. Spinal dorsal nel blockers – is perhaps one of the key hurdles al ion channel accessory proteins on screening sub- horn calcium channel ␣2␦-1 that has contributed to the recent failings in dis- strates. These are then interrogated with fluores- subunit upregulation covery of selective ion channel drugs (see Figure 1). cently labelled interaction domains of the pore- contributes to peripheral As a consequence of this, alternative mechanisms forming domain of the ion channels themselves in nerve injury induced tactile for modulating ion channel function are being the presence of test compounds. LEPTICS® has . J. Neurosci., 24, 8494-8499, (2004). exploited in order to increase the subtype selectivi- already been used to identify novel Cav channel 20 Kanumilli, S, Ginham, R, ty of potential ion channel drugs. modulators following immobilisation of Cav‚ Stafford, S, Hogg, D and accessory protein subunits which were interrogat- Kozlowski, R. In vitro assay for Emerging screening strategies – ion ed with the alpha interaction domain (AID) of the identifying modulators of Cav ␣ ␤ channel accessory protein drug ␣1 subunit of the Cav2.2 channel20. Older less effi- channel 1– subunit interactions. J. Physiol., discovery cient technologies have also been used to similar 568P,PC16,(2005). Given the paucity of new drugs arising from tar- effect. Young et al21 developed a counterselection geting of the pore-forming domain of ion channels, yeast-two hybrid assay, based on the intracellular strategies have been developed to consider modu- linker between domain I and II of the ␣1 subunit of latory sites on the ion channel complex. There is a Cav2.2 and the Cav␤3 subunit, to detect com- plethora of accessory proteins whose role is to fine pounds that would inhibit this interaction. tune the total current flowing through the ion Subsequently, hit compounds were also shown to Continued on page 90

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Continued from page 89

21 Young, K, Lin, S, Sun, L, Lee, E, Modi, M, Hellings, S, Husbands, M, Ozenberger, B and Franco, R. Identification of a calcium using a high throughput yeast two-hybrid screen. Nat. Biotechnol., 16, 946-50, (1998). 22 Rettig, J, Heinemann, SH, Wunder, F, Lorra, C, Parcej, DN, Dolly, JO and Pongs, O. Inactivation properties of voltage-gated K+ channels altered by presence of beta- subunit. Nature, 369, 289-294, (1994). 23 Heinemann, SH, Rettig, J, Graack, HR and Pongs, O. Figure 1: Homology of the K+ channel pore region presents a hurdle in the design of channel-specific blockers Functional characterization of a) Typical structure of the pore region of a voltage-gated K+ (Kv) channel elucidated by the X-ray crystal structure of Kv channel beta-subunits from KcsA3 (Only two of the four identical subunits are shown.) The pore helices are labelled P,and the central cavity is rat brain. J. Physiol., 493, 625- indicated by a red asterisk.The green triangle points to the position of the two threonine residues located at the base 633, (1996). of the pore helix.The side chains of these threonine residues and a few residues (red triangles) of the S6 helices face 24 Morales, MJ, Castellino, CR, the central cavity and are common sites of interaction with pore blockers Crews,AL, Rasmusson, RL and b) The sequence alignment of key regions near the selectivity filter and S6 domains of several Kv channels are shown. Strauss, HC.A novel beta Residues that face the central cavity of the channel are shaded in red. Blockers of Kv1.528, KCNQ129 and human ether- subunit increases rate of a-go-go-related gene HERG30 channels have been reported to interact with these residues.The key residues of Kv1- inactivation of specific voltage- Kv4 channels are identical, illustrating the difficulty in discovering specific drugs for these channels. Drugs that effect gated potassium channel alpha channel gating or block through alternative mechanisms, such as (i) binding to variable domains of the outer pore subunits. J. Biol. Chem., 270, region of the channel, (for example, the turret structure in part a) or (ii) binding to ion channel accessory proteins; 6272-6277, (1995). may lead to greater selectivity for target channels 25 Gulbis, JM, Zhou, M, Mann, © (2003) Macmillan Magazines Ltd. Part a) modified, with permission, from Jiang et al31 S and MacKinnon, R. Structure of the cytoplasmic beta subunit-T1 assembly of voltage-dependent K+ inhibit N-type calcium channels in superior cervi- kinetics of the potassium currents would appear to channels. Science, 289, 123-7, cal ganglion (SCG) neurones and display selectivi- be Kv␤-subunit specific. For example, co-expres- (2000). ty over structurally-related sodium channels in sion of either the Kv␤2 or Kv␤3 subunits with Kv␣ 26 Stafford, S, Ginham, R, Davies,ARL, Lawton, G, Boden, SCG neurones and cloned Kv1.2 and Kv2.1 potas- pore forming domain does not alter inactivation 24 PR and Kozlowski, RZ. In vitro sium channels expressed in mammalian cells, sug- rates . On this basis, Lectus, using LEPTICS®, assay for identifying gestive of channel selectivity. has immobilised Kv␤ accessory protein subunits on modulators of Kv channel ␣-␤ The modulatory nature of compounds which act a screening substrate and interrogated them with subunit interactions. J. Physiol., by disrupting the interaction between the pore- different T1 domains (the corresponding Kv1.x 567P,C89, (2005). 27 Zhang, ZH, Rhodes, KJ, forming domain and accessory proteins may channel interaction sites located on the N-terminus 25 Childers,WE,Argentieri,TM indeed provide the basis for an enhanced selectivi- of the ␣ subunit ) to identify novel inhibitors of and Wang, Q. Disinactivation ty profile. However the additional complexity this interaction26. of N-type inactivation of introduced by the protein-protein interaction In an alternative approach to this same target, voltage-gated K channels by an necessitates the use of native cells in conjunction using a high-throughput yeast-two-hybrid screen, erbstatin analogue. J. Biol. 27 Chem., 279, 29226-30, (2004). with classical electrophysiology for detailed analy- Zhang et al have also identified small molecules 28 Decher, N, Pirard, B, sis of the often subtle effects mediated via ion which inhibit the interaction domain between the Bundis, F, Peukert, S, channel accessory proteins. inactivation region of either Kv␤1 subunits or the Baringhaus, KH, Busch,AE, intrinsic inactivation region of Kv1.4 channels Steinmeyer, K and Sanguinetti, Potassium channels with a putative acceptor site located on the S4-S5 MC. Molecular basis for Kv1.5 ␣ channel block: conservation of The second example is one of the most widely intracellular loop of the channel subunit. drug binding sites among studied ion channel accessory proteins, the Kv␤ These approaches demonstrate significant voltage-gated K+ channels. J. subunit of the delayed rectifier (Kv1.x) potassium advancement in developing alternative strategies Biol. Chem., 279, 394–400, channels. Currents measured through the ␣ sub- for modulation of ion channel function and collec- (2004). unit Kv1.x channels show an increased rate of tively offer a differentiated approach to existing inactivation when co-expressed with the Kv␤1 sub- screening technologies for the identification of new Continued on page 92 units in Xenopus22,23. These alterations in the classes of ion channel modulators.

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Continued from page 90 Conclusions actively involved in the management of Lectus Advancements in structural and molecular Therapeutics since 2004, he became full-time 29 Seebohm, G, Chen, J, Strutz, coupled with those in screening technology should Director of Biology in April 2006 following the N, Culberson, C, Lerche, C and Sanguinetti, MC. Molecular help overcome the present hiatus in development of acquisition of NeuroServe by Lectus. determinants of KCNQ1 novel ion channel therapeutics. Additionally, alter- channel block by a native approaches to the targeting of ion channels, Dr Geoff Lawton is Research Director of Lectus . Mol. via modulation of their accessory proteins, will also Therapeutics Limited. Dr Lawton has extensive Pharmacol., 64, 70–77, (2003). add to the repertoire of strategies available for iden- experience in drug discovery across many thera- 30 Mitcheson, JS, Chen, J, Lin, M, Culberson, C and tifying compounds differentiated from those that peutic areas with Roche and is co-inventor of a Sanguinetti, MC.A structural have so far experienced limited success in develop- marketed drug (Cilazapril). His roles at Roche basis for drug-induced long ment. Given the current investment in this field, the included Head of Medicinal Chemistry and QT syndrome. Proc. Natl next decade has the potential to yield therapeutics Director of Chemistry within Roche UK, and Acad. Sci. USA, 97, targeting ion channels in a broad range of disease Vice-president Chemistry and Preclinical 12329–12333, (2000). 31 Jiang,Y. et al.The open pore indications that remain ineffectively treated includ- Sciences within Roche Bioscience, Palo Alto, conformation of potassium ing overactive bladder, pain, autoimmune disor- USA. Prior to joining Lectus, Dr Lawton provid- channels. Nature 417, 523–526 ders, osteoporosis and COPD. DDW ed evaluation and advice on drug discovery proj- (2002). ects as an independent consultant for a number Dr Dayle S. Hogg is the Commercial Manager at of different companies. Lectus Therapeutics Limited. Dayle plays a key role in developing strategic alliances, pursuing Dr Roland Z. Kozlowski is the principal founder partnering/collaborative opportunities, evaluating and CEO of Lectus Therapeutics Limited. He has new commercial opportunities and securing com- led the company through both seed and a recent mercial deals with service providers. Dayle was £8.2 million series A financing round. As part of the part of the team that secured the strategic invest- financing strategy of the business he executed a ment from Takeda Research Investment and also strategic alliance with Takeda Research Investment, the recent Series A financing for the company. the investment arm of Takeda Pharmaceutical Dayle previously worked within Business Company. Roland was until December 2002 CEO Development at Proteomic Ltd, whose core and principal founder of Sense Proteomic Limited. business was the development and sale of func- At Sense he raised a total of £5.75 million from pri- tional protein array products. Dayle received a BSc vate equity sources and grew the business from a degree from the University of Leeds and a DPhil virtual start-up to a company operating with 30 from the University of Oxford. At a research level, staff. Under his leadership the company produced Dayle trained as an electrophysiologist where his the world’s first functional proteomics array prod- interests centred the role of ion channels in regu- uct. Having developed the strategy for the business lating pulmonary blood flow. he led the Sense team to conclude a sale of the com- pany to Procognia Limited as part of a $4 million Dr Philip Boden worked for Warner-Lambert financing of the combined businesses in December (now part of Pfizer) from 1984 to 1999. In that 2002. Before that, he was pivotal to the initiation time he established the electrophysiology laborato- and success of Oxford Molecular’s Drug Discovery ries in Cambridge UK which pioneered the use of Division where he conducted business development brain slices for drug testing. Dr Boden also served for the company and won its cornerstone drug dis- on project teams for many pro- covery deal with Yamanouchi Pharmaceutical Corp grammes and established a group with a research (Japan). Roland is on the Main Board of the Bio focus on molecular mechanisms underlying neu- Industry Association and is a member of the facul- ropeptide receptor/ion channel interaction in the ty of the University of Bristol where he advises on central . Studies on enterprise strategy. Roland is an inventor on six Responsive neurons were reported from Dr patent applications in the proteomics arena and has Boden’s laboratory in 1990 and he collaborated more than 50 peer reviewed scientific publications with members of the Pharmacology Department at in the ion channels field. He holds a First Class the University of Cambridge, UK in further studies Honours Degree in Pharmacology from the of these, leading to the first reports of the existence University of Bath and a PhD in Pharmacology of ATP-K channels in rat brain. Dr Boden left his from the University of Cambridge. He formerly ran position as Senior Group Leader in Molecular a research group in the Pharmacology Department Neurobiology at Warner-Lambert to establish his at the University of Oxford and was a fellow of own company, NeuroServe, in 2000. Having been Brasenose College.

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