20082018
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Personal profile

Research

Key achievements over last 5 years:

Validation of N-myristoyltransferase as a drug target in human African trypanosomiasis and development of compounds which are potential candidates for stage 1 disease.

1. Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors. Brand, S.; Cleghorn, L. A. T.; McElroy, S. P.; Robinson, D. A.; Smith, V. C.; Hallyburton, I.; Harrison, J. R.; Norcross, N. R.; Norval, S.; Spinks, S.; Stojanovski, L.; Torrie, L. S.; Frearson, J. A.; Brenk, R.; Fairlamb, A. H.; Ferguson, M. A. J.; Read, K. D.; Wyatt, P. G.; Gilbert, I. H. J. Med. Chem. 2012, 55, 140-152.

2. N-myristoyltransferase inhibitors as new leads to treat sleeping sickness. Frearson, J. A.; Brand, S.; McElroy, S. P.; Cleghorn, L. A. T.; Smid, O.; Stojanovski, L.; Price, H. P.; Guther, M. L. S.; Torrie, L. S.; Robinson, D. A.; Hallyburton, I.; Mpamhanga, C. P.; Brannigan, J. A.; Wilkinson, A. J.; Hodgkinson, M.; Hui, R.; Qiu, W.; Raimi, O. G.; Van Aalten, D. M. F.; Brenk, R.; Gilbert, I. H.; Read, K. D.; Fairlamb, A. H.; Ferguson, M. A. J.; Smith, D. F.; Wyatt, P. G. Nature, 2010, 464, 728-732.

Development of potential preclinical candidates for African animal trypanosomiasis.

Unpublished.

Development of compounds to late leads status for malaria.

Unpublished.

Key player in redefining CNS drug discovery lead optimization process.

Central nervous system drug disposition: The relationship between in situ brain permeability and brain free fraction. Summerfield S, Read KD, Begley DJ, Obradovic T, Hidalgo IJ, Coggon S, Lewis AV, Porter RA and Jeffrey P. (2007). JPET 322, 205-213

Receptor occupancy and brain free fraction. Watson JM, Wright S, Lucas A, Clarke KL, Viggers J, Cheetham S, Jeffrey P, Porter RA and Read KD (2009). Drug Metabolism and Disposition 37, 753-760

Assessing brain free fraction in early drug discovery. Read KD and Braggio S (2010). Expert Opin. Drug Metab. Toxicol. 6 (3), 337-344

Combining PET biodistribution and equilibrium dialysis assays to assess the free brain concentration and BBB transport of CNS drugs. Gunn RN, Summerfield SG, Salinas CA, Read KD, Guo Q, Searle GE, Parker CA, Jeffrey P, Laruelle M (2012). J. Cereb Blood Flow Metab. 32(5):874-83

Drug repositioning.

The Anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis. Wyllie S, Patterson S, Stojanovski L, Simeons FRC, Norval S, Kime R, Read KD  and Fairlamb AH (2012). Science Translational Medicine, 4, 1-7

 

Grants awarded over last 5 years:

GALVmed, April 2012 to August 2013; £398K. Discovery and development of new drugs for treatment/ prevention of Trypanosomiasis in cattle. PIs Kevin Read and Ian Gilbert

Scottish funding council and TPP Global Development Ltd.  Jobs, health and wealth. November 2011 to September 2013. PIs: Paul Wyatt, David Gray, Kevin Read, Andrew Hopkins. Full award value: £825,000

Wellcome Trust; April 2011 to March 2016; £8.6M; Drug Discovery for Tropical Diseases; PIs: Paul Wyatt, Michael Ferguson and Alan Fairlamb; Co-applicants: Daan van Aalten, Ian Gilbert, Ruth Brenk, Kevin Read. Wellcome Trust Reference 092340.

Drug Discovery for Mycobacterium tuberculosis; 1st March 2011 to 28th February 2014. PI: Paul Wyatt; Co-applicants Ian Gilbert, Kevin Read. Funded in part by a Grant from the Foundation for the National Institutes of Health with support from the Bill and Melinda Gates Foundation. Total consortium grant $6,781,984. Dundee component £770,248

Medicines for Malaria Venture; Discovery and Optimisation of Phenotypic Hits; 1st April 2010 to 31st December 2013. US$1,636,000. PIs: Ian Gilbert and Kevin Read; Coapplicants: Alan Fairlamb, David Gray, Paul Wyatt.

MRC DPFS devolved portfolio. The Development of N-Myristoyl transferase Inhibitors as Anticancer Agents. April 2010 to March 2011.  Paul Wyatt (PI), co-applicants: Kevin Read, Alastair Thompson, David Blake (Cyclacel). Full award value: £255,744

MRC DPFS devolved portfolio. Translating a Portfolio of Novel Biological Targets towards Therapeutics. 1st October 2009 to 30th September 2011.  PI: Paul Wyatt. Co-applicant Kevin Read. Full award value: £1,087,071

Drugs for Neglected Diseases inititiative; Identification of Drug Candidates to Treat Leishmaniasis; 1st April 2009 to 31st March 2014; £1,810,000. PI: Paul G. Wyatt; Co-applicants, A.H. Fairlamb, I.H. Gilbert, K.D. Read.

European Union; Jan 2009 to June 2012; total grant €2.6M/ Dundee component €508K; Nucleobase derivatives as drugs against trypanosomal diseases (Trypobase). Partners Consejo Superior da Investigaciones Cientificas (coordinator), University of Dundee, Medivir, University of York, Swiss Tropical Institute, Syngene, Institute Pasteur Montevideo.

 

Biography

I have over 22 years of experience working in the pharmaceutical industry as a DMPK scientist, 16 years of which have been in CNS drug discovery. My first degree in applied biology was obtained from Coventry polytechnic and my PhD (evaluation of blood-brain barrier models for measurement and prediction of brain drug penetration) was obtained from Kings College, London.

I started my career in 1989 as a DMPK scientist with Huntingdon Research centre gaining experience in the use of radionuclides in drug metabolism studies and carrying out ADME and PK studies in pre-clinical species in support of various drug development projects.  In 1992 I joined the DMPK division in Glaxo Group Research in the UK, gaining extensive experience in drug discovery support. This involved optimisation of new chemical entities emerging from the projects with respect to their in vitro/in vivo metabolic stability, absorption, blood-brain barrier penetration and pharmacokinetic/pharmacodynamic profiles.

In 1996 I became a core member of a multi-disciplinary and multi-national research team within GlaxoWellcome, responsible for the development, evaluation and implementation of appropriate technologies to ensure “efficacious” penetration of the CNS. I helped lead this group and had a pivotal role in setting strategy, generating data and bringing knowledge to bear in all CNS drug discovery projects.

In 2001 I moved to GlaxoSmithKline, Italy as a Research Leader with management responsibility for 9 graduate and post-graduate scientists. I was responsible for the establishment of an in vitro DMPK laboratory with capacity to support all Verona, Italy and Harlow, UK, Psychiatry CEDD exploratory and lead optimisation (LO) programmes.  A number of assays were developed and implemented, including CYP inhibition, metabolism dependent inhibition, intrinsic clearance, reactive metabolite assessment (GSH trapping assay), reaction phenotyping, tissue and protein binding and a Pgp substrate assay.  I was accountable for high quality, rapid in vitro support to all drug discovery programmes within the Psychiatry CEDD, UK and Italy.

In April 2004 I was promoted to Senior Research Leader and my responsibility shifted from the in vitro team to manage the DMPK lead optimisation team.  I had management responsibility for 8 scientists, accountable for strategy and co-ordination of all DMPK support to all Verona CNS drug discovery LO programmes. 

I was a GSK programme leader for a full lead optimisation programme up to candidate selection in major depressive disorder and a deputy programme leader on two other psychiatry LO programmes from 2004 through end 2007.

In January 2008, I moved to the School of Life Sciences, University of Dundee, to establish a DMPK group.  I have now recruited six scientists and implemented industry standard assays coupled with state of the art UPLCMSMS technology for supporting hit to lead and lead optimisation programmes.  The capabilities now available at Dundee include in silico ADME models together with a range of in vitro and in vivo tools, selected in order to provide a good overall assessment of the developability profile of compounds early in the lead optimisation process.

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Research Output 2008 2018

2,4-Diamino-6-methylpyrimidines for the potential treatment of Chagas’ disease

Thomas, M. G., De Rycker, M., Cotillo Torrejon, I., Thomas, J., Riley, J., Spinks, D., Read, K. D., Miles, T. J., Gilbert, I. H. & Wyatt, P. G., 1 Oct 2018, In : Bioorganic & Medicinal Chemistry Letters. 28, 18, p. 3025-3030 6 p.

Research output: Contribution to journalArticle

Chagas Disease
Parasites
Nifurtimox
Trypanosoma cruzi
Screening
2 Citations

2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis: Structure-Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization

Murugesan, D., Ray, P. C., Bayliss, T., Prosser, G. A., Harrison, J. R., Green, K., Soares De Melo, C., Feng, T. S., Street, L. J., Chibale, K., Warner, D. F., Mizrahi, V., Epemolu, O., Scullion, P., Ellis, L., Riley, J., Shishikura, Y., Ferguson, L., Osuna-Cabello, M., Read, K. D. & 10 othersGreen, S. R., Lamprecht, D. A., Steyn, A. J. C., Ioerger, T. R., Sacchettini, J., Rhee, K. Y., Arora, K., Barry, C. E., Wyatt, P. G. & Boshoff, H. I. M., 8 Jun 2018, In : ACS Infectious Diseases. 4, 6, p. 954-969 16 p.

Research output: Contribution to journalArticle

Open Access
File
Quinazolinones
Structure-Activity Relationship
Mycobacterium tuberculosis
Adenosine Triphosphate
Allosteric Site
1 Citations

A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors

Harrison, J. R., Brand, S., Smith, V., Robinson, D. A., Thompson, S., Smith, A., Davies, K., Mok, N., Torrie, L. S., Collie, I., Hallyburton, I., Norval, S., Simeons, F. R. C., Stojanovski, L., Frearson, J. A., Brenk, R., Wyatt, P. G., Gilbert, I. H. & Read, K. D., 12 Sep 2018, In : Journal of Medicinal Chemistry. 61, 18, p. 8374–8389 16 p.

Research output: Contribution to journalArticle

Open Access
File
African Trypanosomiasis
Trypanosoma brucei brucei
Crystallography
Central Nervous System Diseases
Peripheral Nervous System
1 Citations
Open Access
File
Metabolites
Drug Users
Metabolism
Opioid Analgesics
Urine
2 Citations

Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis

Wyllie, S., Thomas, M., Patterson, S., Crouch, S., De Rycker, M., Lowe, R., Gresham, S., Urbaniak, M. D., Otto, T. D., Stojanovski, L., Simeons, F. R. C., Manthri, S., MacLean, L. M., Zuccotto, F., Homeyer, N., Pflaumer, H., Boesche, M., Sastry, L., Connolly, P., Albrecht, S. & 12 othersBerriman, M., Drewes, G., Gray, D. W., Ghidelli-Disse, S., Dixon, S., Fiandor, J. M., Wyatt, P. G., Ferguson, M. A. J., Fairlamb, A. H., Miles, T. J., Read, K. D. & Gilbert, I. H., 25 Jul 2018, In : Nature. 560, 7717, p. 192-197 6 p.

Research output: Contribution to journalArticle

Visceral Leishmaniasis
Cyclin-Dependent Kinases
Pharmaceutical Preparations
Toxicology
Parasites

Press / Media

Tuberculosis drug may also target visceral leishmaniasis

Alan Fairlamb & Kevin Read

24/05/16

1 item of media coverage

Press/Media: Research

Automated design for Drug Discovery

Andrew Hopkins, Suzanne Norval, Jeremy Besnard, Laste Stojanovski, Richard Bickerton, Kevin Read & Ian Gilbert

13/12/12

1 item of media coverage

Press/Media: Research

Thesis

Spontaneous Raman spectroscopy: Exploring applicability in drug discovery and the medical sciences

Author: Rabl, T., 2018

Supervisor: Read, K. (Supervisor) & McGloin, D. (Supervisor)

Student thesis: Doctoral ThesisDoctor of Philosophy