Yr Athro John Atack
Cyfarwyddwr, y Sefydliad Darganfod Meddyginiaethau
- atackj@cardiff.ac.uk
- +44 (0)29 2087 6983
- Y Prif Adeilad, Plas y Parc, Caerdydd, CF10 3AT
Trosolwg
Rwy'n ffarmacolegydd molecwlaidd gyda dros 25 mlynedd o brofiad o ddarganfod cyffuriau, ym maes y niwrowyddorau yn bennaf. Yn ystod y cyfnod hwn rydw i wedi cyfrannu at gamau cyntaf y broses darganfod cyffuriau (nodi targed a dilysu'r targed) ac wedi parhau i gyfrannu hyd at dreialon clinigol Cam 1 a Cham 2.
Rydw i wedi gweithio ar nifer o wahanol fathau o dargedau cyffuriau (ensymau, derbynyddion sydd wedi eu cyplu â phroteinau G, a sianeli ïonig) sy'n cwmpasu amrywiaeth o glefydau niwro-ddirywiol (e.e. clefydau Alzheimer, Huntington a Parkinson) ac anhwylderau seiciatrig (anhwylder deubegynol, sgitsoffrenia, anhwylder gorbryder cyffredinol, iselder). Mae gen i ddiddordeb penodol yn elfennau cyn-clinigol y broses darganfod cyffuriau, sy'n rhoi hyder bod cyffur posibl yn gallu cysylltu â'r targed a chynhyrchu allbwn gweithredol mewn bod dynol.
Beth yw fy hoff gyffur a mecanwaith gweithredu? Byddai'n rhaid i mi ddweud diasepam a'r derbynnydd GABAA ... Neu efallai cetamin a'r derbynnydd NMDA ... Neu lithiwm a sut bynnag mae hwnnw'n gweithio mewn anhwylder deubegynol ... Heb sôn am ddonepesil, felly wna' i ddim.
Bywgraffiad
Ar ôl cwblhau PhD mewn patholeg niwrogemegol yn Adran Patholeg Ysbyty Cyffredinol Newcastle, gweithiais am 5 mlynedd (1984-89) yn Labordy Niwrowyddorau'r Sefydliad Cenedlaethol ar gyfer Oedi ar gampws y Sefydliadu Iechyd Cenedlaethol (NIH) ym Methesda, Maryland, yn astudio newidiadau cyn ac ar ôl marwolaeth mewn niwrogemeg cleifion â chlefyd Alzheimer a syndrom Down.
Yn ystod fy nghyfnod yn NIH, dechreuais brosiect oedd yn edrych ar ddatblygu atalwyr acetylcholinesterase ar gyfer trin clefyd Alzheimer. Yna, ymunais â Chanolfan Ymchwil Niwrowyddorau Merck Sharp a Dohme yn Harlow lle gweithiais rhwng 1989–2006 ar amrywiaeth o agweddau in vitro ac in vivo ar ddarganfod cyffuriau ym maes y niwrowyddorau. Pan gaeodd y safle o ganlyniad anuniongyrchol i'r ffaith y cafodd Vioxx, cyffur pwysig cwmni Merck, ei dynnu oddi ar y farchnad, ymunais â Janssen Pharmaceuticals, sef cangen fferyllol Johnson & Johnson, lle bues yn gweithio rhwng 2006 a 2012 (yn La Jolla i ddechrau, ac yna, oherwydd y cwrw, sglodion a siocled, yn Beerse, Gwlad Belg).
Gadewais y diwydiant fferyllol i ymuno â Phrifysgol Sussex i helpu i sefydlu, gyda'r Athro Simon Ward, Canolfan Darganfod Cyffuriau Sussex, a gyda chymorth yr Athro Martin Gosling hefyd datblygodd y ganolfan enw da am ddarganfod cyffuriau ym maes y niwrowyddorau a ffarmacoleg sianeli ïonig yn benodol.
Yn haf 2017, dewisodd Simon a minnau symud i Gaerdydd. Cawsom ein denu gan y gwaith rhagorol ym maes y mecanwaith clefydau a gwyddorau clinigol, ynghyd ag ansawdd ac ysbryd cydweithredol yr ymchwilwyr y byddwn yn cydweithio â nhw. Fodd bynnag, rydym yn dal i fod mewn cysylltiad â Martin, sy'n gydweithiwr allweddol ac yn ein galluogi i ehangu'r diddordeb sydd gennym mewn ffarmacoleg sianeli ïonig.
Cyhoeddiadau
2021
- Manzo, M. A.et al. 2021. Inhibition of a tonic inhibitory conductance in mouse hippocampal neurones by negative allosteric modulators of α5 subunit-containing γ-aminobutyric acid type A receptors: implications for treating cognitive deficits. British Journal of Anaesthesia 126(3), pp. 674-683. (10.1016/j.bja.2020.11.032)
2020
- Fenn, G.et al. 2020. Crystallization and structure of ebselen bound to cysteine 141 of human inositol monophosphatase (IMPase). Acta Crystallographica Section F: Structural Biology Communications F76(10), pp. 469-476. (10.1107/S2053230X20011310)
- Maramai, S.et al. 2020. Subtype selective y-Aminobutyric acid type A receptor (GABAAR) modulators acting at the benzodiazepine binding site: An update. Journal of Medicinal Chemistry 63(7), pp. 3425-3446. (10.1021/acs.jmedchem.9b01312)
- Koulouris, C. R.et al. 2020. Conformational flexibility within the small domain of human serine racemase. Acta Crystallographica Section F: Structural Biology Communications 76(2), pp. 65-73. (10.1107/S2053230X20001193)
- Ward, S. E.et al. 2020. Pharmacological characterisation of MDI-222, a novel AMPA receptor positive allosteric modulator with an improved safety profile. Journal of Psychopharmacology 34(1), pp. 93-102. (10.1177/0269881119872198)
2019
- Raulin, A.et al. 2019. The molecular basis for apolipoprotein E4 as the major risk factor for late-onset Alzheimer's disease. Journal of Molecular Biology 431(12), pp. 2248-2265. (10.1016/j.jmb.2019.04.019)
- Kraft, L., Serpell, L. C. and Atack, J. R. 2019. A biophysical approach to the identification of novel ApoE chemical probes. Biomolecules 9(2), article number: 48. (10.3390/biom9020048)
2018
- Noble, J. W.et al. 2018. The X-ray structure of human calbindin-D28K: an improved model. Acta Crystallographica. Section D: Structural Biology 74(10), pp. 1008-1014. (10.1107/S2059798318011610)
- Duke, A. N.et al. 2018. Evidence that sedative effects of benzodiazepines involve unexpected GABAA receptor subtypes: Quantitative observation studies in rhesus monkeys. Journal of Pharmacology and Experimental Therapeutics 366(1), pp. 145-157. (10.1124/jpet.118.249250)
- Kraft, L.et al. 2018. Co-crystallization of human inositol monophosphatase with the lithium mimetic L-690,330. Acta Crystallographica. Section D: Structural Biology 74(10), pp. 973. (10.1107/S2059798318010380)
2017
- West, R. A.et al. 2017. African trypanosomiasis: Synthesis & SAR enabling novel drug discovery of ubiquinol mimics for trypanosome alternative oxidase. European Journal of Medicinal Chemistry 141, pp. 676-689. (10.1016/j.ejmech.2017.09.067)
- Khan, R.et al. 2017. Combining Sanford Arylations on Benzodiazepines with the nuisance effect. Advanced Synthesis & Catalysis 359(18), pp. 3261-3269. (10.1002/adsc.201700626)
2016
- Hornyak, P.et al. 2016. Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2. Biochemical Journal 473(13), pp. 1869-1879. (10.1042/BCJ20160180)
- Gaekens, T.et al. 2016. Lipophilic nalmefene prodrugs to achieve a one-month sustained release. Journal of Controlled Release 232, pp. 196. (10.1016/j.jconrel.2016.04.029)
2015
- Spurny, R.et al. 2015. Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the α7 nicotinic acetylcholine receptor. Proceedings of the National Academy of Sciences of the United States of America 112(19), article number: E2543. (10.1073/pnas.1418289112)
2014
- Atack, J. R.et al. 2014. JNJ-40255293, a novel adenosine A2A/A1 antagonist with efficacy in preclinical models of Parkinson's disease. ACS Chemical Neuroscience 5(10), pp. 1005-1019. (10.1021/cn5001606)
- Walker, S.et al. 2014. Development of an oligonucleotide-based fluorescence assay for the identification of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors. Analytical Biochemistry 454, pp. 17-22. (10.1016/j.ab.2014.03.004)
- Lavreysen, H. and Atack, J. 2014. Receptors: Functional assays. In: Stolerman, I. P. and Price, L. H. eds. Encyclopedia of Psychopharmacology. Berlin and Heidelberg: Springer, (10.1007/978-3-642-27772-6_208-2)
2013
- Lavreysen, H.et al. 2013. Pharmacological characterization of JNJ-40068782, a new potent, selective, and systemically active positive allosteric modulator of the mGlu2 receptor and its radioligand [3H]JNJ-40068782. Journal of Pharmacology and Experimental Therapeutics 346(3), pp. 514-527. (10.1124/jpet.113.204990)
- Shinday, N. M.et al. 2013. Reinforcing effects Of compounds lacking intrinsic efficacy at α1 subunit-containing GABAA receptor subtypes in midazolam- but not cocaine-experienced Rhesus Monkeys. Neuropsychopharmacology 38(6), pp. 1006-1014. (10.1038/npp.2012.265)
2012
- Langlois, X.et al. 2012. Pharmacology of JNJ-37822681, a specific and fast-dissociating D2 antagonist for the treatment of schizophrenia. Journal of Pharmacology and Experimental Therapeutics 342(1), pp. 91-105. (10.1124/jpet.111.190702)
- Mirza, N. R., Atack, J. and Wafford, K. 2012. Receptor subtypes: novel targets for novel medicines. Advances in Pharmacological Sciences 2012, article number: 529861. (10.1155/2012/529861)
2011
- Swanson, D. M.et al. 2011. The discovery and synthesis of JNJ 31020028, a small molecule antagonist of the Neuropeptide Y Y2 receptor. Bioorganic and Medicinal Chemistry Letters 21(18), pp. 5552-5556. (10.1016/j.bmcl.2011.06.136)
- Fischer, B. D.et al. 2011. Contribution of GABAA receptors containing α3 subunits to the therapeutic-related and side effects of benzodiazepine-type drugs in monkeys. Psychopharmacology 215(2), pp. 311-319. (10.1007/s00213-010-2142-y)
- Atack, J.et al. 2011. MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans. Journal of Psychopharmacology 25(3), pp. 314-328. (10.1177/0269881109354927)
- Atack, J.et al. 2011. Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist. Journal of Psychopharmacology 25(3), pp. 329-344. (10.1177/0269881109354928)
- Atack, J. 2011. GABAA receptor subtype-selective modulators. II. α5-selective inverse agonists for cognition enhancement. Current Topics in Medicinal Chemistry 11(9), pp. 1203-1214. (10.2174/156802611795371314)
- Atack, J. 2011. GABAA receptor subtype-selective modulators. I. α2/α3-selective agonists as non-sedating anxiolytics. Current Topics in Medicinal Chemistry 11(9), pp. 1176-1202. (10.2174/156802611795371350)
2010
- Eng, W.et al. 2010. Occupancy of human brain GABAA receptors by the novel α5 subtype-selective benzodiazepine site inverse agonist α5IA as measured using [11C]flumazenil PET imaging. Neuropharmacology 59(7-8), pp. 635-639. (10.1016/j.neuropharm.2010.07.024)
- Atack, J. R. 2010. Development of subtype-selective GABAA receptor compounds for the treatment of anxiety, sleep disorders and epilepsy. In: Monti, J. M., Pandi-Perumal, S. R. and Mohler, H. eds. GABA and Sleep. Basel: Springer, pp. 25-72., (10.1007/978-3-0346-0226-6_2)
- Letavic, M. A.et al. 2010. Pre-clinical characterization of aryloxypyridine amides as histamine H3 receptor antagonists: Identification of candidates for clinical development. Bioorganic and Medicinal Chemistry Letters 20(14), pp. 4210-4214. (10.1016/j.bmcl.2010.05.041)
- Stocking, E. M.et al. 2010. Novel substituted pyrrolidines are high affinity histamine H3 receptor antagonists. Bioorganic and Medicinal Chemistry Letters 20(9), pp. 2755-2760. (10.1016/j.bmcl.2010.03.071)
- Dixon, C. I.et al. 2010. Cocaine effects on mouse incentive-learning and human addiction are linked to α2 subunit-containing GABAA receptors. Proceedings of the National Academy of Sciences 107(5), pp. 2289-2294. (10.1073/pnas.0910117107)
- Licata, S. C.et al. 2010. Discriminative stimulus effects of L-838,417 (7-tert-butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine): Role of GABAA receptor subtypes. Neuropharmacology 58(2), pp. 357-364. (10.1016/j.neuropharm.2009.10.004)
- Shoblock, J. R.et al. 2010. In vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a selective brain penetrant small molecule antagonist of the neuropeptide Y Y2 receptor. Psychopharmacology 208(2), pp. 265-277. (10.1007/s00213-009-1726-x)
- Atack, J. R. 2010. Preclinical and clinical pharmacology of the GABAA receptor α5 subtype-selective inverse agonist α5IA. Pharmacology and Therapeutics 125(1), pp. 11-26. (10.1016/j.pharmthera.2009.09.001)
- Ator, N. A.et al. 2010. Reducing abuse liability of GABAA/Benzodiazepine ligands via selective partial agonist efficacy at α1 and α2/3 subtypes. Journal of Pharmacology and Experimental Therapeutics 332(1), pp. 4-16. (10.1124/jpet.109.158303)
- Atack, J. R.et al. 2010. Benzodiazepine binding site occupancy by the Novel GABAA receptor subtype-selective drug 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) in rats, primates, and humans. Journal of Pharmacology and Experimental Therapeutics 332(1), pp. 17-25. (10.1124/jpet.109.157909)
2009
- Atack, J. R. 2009. GABAA receptor α2/α3 subtype-selective modulators as potential nonsedating anxiolytics. Current Topics in Behavioral Neuroscience 2, pp. 331-360. (10.1007/7854_2009_30)
Ar hyn o bryd rwy'n cymryd rhan mewn prosiectau sy'n adnabod moleciwlau sy'n rhyngweithio ag is-deipiau'r derbynnydd GABBA neu is-deip AMPA y derbynnydd glwtamad. Mae'r prosiectau'n cynnwys timau amlddisgyblaethol o wyddonwyr sy'n defnyddio cemeg feddygol arloesol (dan arweiniad yr Athro Simon Ward) ac electroffisioleg (yr Athro Martin Gosling o Brifysgol Sussex a'r Athro Jerry Lambert o Brifysgol Dundee) ynghyd â nifer o bartneriaid ym myd diwydiant (e.e. GSK ac AstraZeneca).
Rydw i hefyd yn cymryd rhan mewn nifer o brosiectau yn eu cyfnodau cynnar sy'n astudio mecanwaith gweithredu lithiwm a rôl ApoE4 mewn clefyd Alzheimer ynghyd â dulliau newydd o fodiwleiddio NMDA a gweithrediad sianel ïonig cainad glwtamad.
Yr hyn sy'n fy ysgogi yw fy awydd i ddatblygu triniaethau newydd ar gyfer anhwylderau niwroddirywiol a seiciatrig sy'n cael effaith enfawr ar gymaint o'n teuluoedd, ac le mae anghenion meddygol sylweddol nad ydynt yn cael eu diwallu.
