With substantial input into all drug discovery projects in the DDU, I have a strong track record of success in delivery of high quality drug candidates.  Since moving to the DDU, notable examples include:

Validation of N-myristoyltransferase as a drug target in human African trypanosomiasis and development of compounds which are potential preclinical candidates for stage 1 only or stage 1 and stage 2 disease. One of these late leads has been subsequently re-purposed into cancer and is currently in Phase 1 clinical trials.

• Frearson, J. A., Brand, S., McElroy, S. P., Cleghorn, L. A., Smid, O., Stojanovski, L., Price, H. P., Guther, M. L., 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., Brenk, R., Gilbert, I. H., Read, K.D., Fairlamb, A. H., Ferguson, M. A., Smith, D. F. and Wyatt, P.G. (2010) N-myristoyltransferase inhibitors as new leads to treat sleeping sickness. Nature. 464, 728-732
• Brand, S., Norcross, N.R, Thompson, S.,  Harrison, J.R., Smith, V.C., Robinson, D.A., Torrie, L.S., McElroy, S.P., Hallyburton, I., Norval, S., Scullion, P., Stojanovski, L., Simeons, F.R.C., van Aalten, D., Frearson, J.A., Brenk, R., Fairlamb, A.H., Ferguson, M.A.J., Wyatt, P.G., Gilbert,  H. and Read, K.D. (2014). Lead Optimization of a Pyrazole Sulfonamide Series of Trypanosoma brucei N-Myristoyltransferase Inhibitors: Identification and Evaluation of CNS Penetrant Compounds as Potential Treatments for Stage 2 Human African Trypanosomiasis.  J. Med.Chem. 57, 9855-9869
• Beauchamp E, Yap MC, Iyer A, Perinpanayagam MA, Gamma JM, Vincent KM, Lakshmanan M, Raju A, Tergaonkar V, Tan SY, Lim ST, Dong WF, Postovit LM, Read KD, Gray DW, Wyatt PG, Mackey JR, Berthiaume LG (2020). Targeting N-myristoylation for therapy of B-cell lymphomas. Nature Communications, 11, 5348.

Identifying that the Anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis (VL). As a direct consequence of this jointly published work with Alan Fairlambs laboratory, the Drugs for Neglected Diseases initiative (DNDi) initiated phase II clinical trials for VL in Africa.

• Wyllie, S., Patterson, S., Stojanovski, L., Simeons, F. R., Norval, S., Kime, R., Read, K. D. and Fairlamb, A.H. (2012) The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis. Sci Transl Med. 4, 1-7

Co-leading the malaria programme team that delivered the first preclinical development candidate for the DDU in October 2013. (DDD498; www.mmv.org/research-development/rd-portfolio).  MMV project of the year 2014.  Currently starting Phase II clinical trials.

• Baragaña, B., Hallyburton, I., Lee, M. C… 57 other authors, Fidock, D.A., Read, K.D., Gilbert, I.H. (2015) A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature, 522, 315-320
• Baragaña B, Norcross NR, Wilson C, Porzelle A, Hallyburton I, Grimaldi R, Osuna-Cabello M, Norval S, Riley J, Stojanovski L, Simeons FRC, Wyatt P, Delves MJ, Meister S, Duff S, Avery VM, Winzeler EA, Sinden RE, Wittlin S, Frearson JA, Gray DW, Fairlamb AH, Waterson D, Campbell SF, Willis P, Read KD and Gilbert IH (2016). Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy. J. Med. Chem., 59, 9672-9685.

Co-leading the visceral leishmaniasis drug discovery programme in partnership with GSK. This delivered two preclinical development candidates with differing modes of action.  The first entered phase I clinical trials in April 2019 and the second in October 2021.

• Wyllie S, Thomas M,  Patterson S,  Crouch S,  De Rycker M,  Lowe R,  Gresham, S,  Urbaniak MD,  Otto TD,  Stojanovski L,  Simeons FRC,  Manthri S,  MacLean LM,  Zuccotto F,  Homeyer N,  Pflaumer H,  Boesche M,  Sastry L,  Connolly P,  Albrecht S, Berriman M,  Drewes G,  Gray DW,  Ghidelli-Disse S,  Dixon S,  Fiandor JM,  Wyatt PG,  Ferguson MAJ,  Fairlamb AH, Miles TJ, Read KD and Gilbert IH (2018). Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis. Nature, 560, 192-197.
• Thomas MG, De Rycker M, et al….Read KD and Miles TJ (2019). Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis. J. Med. Chem., 62, 1180-1202
• Wyllie S, Brand S, Thomas M, et al……Gilbert IH, Read KD, Marco M and Wyatt PG (2019). Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition. PNAS, 116, 9318-9325.
• Thomas M, Brand S, De Rycker M, Zuccotto F, Lukac I, Dodd PG, Ko E.J, Manthri S, McGonagle K, Osuna-Cabello M, Riley J, Pont C, Simeons F, Stojanovski L, Thomas J, Thompson S, Viayna E, Fiandor JM, Martin J, Wyatt PG, Miles TJ, Read KD, Marco M and Gilbert IH (2021). Scaffold-Hopping Strategy on a Series of Proteasome Inhibitors Led to a Preclinical Candidate for the Treatment of Visceral Leishmaniasis. J. Med. Chem., 64, 5905-5930.

I continue to be involved in a large number of diverse small molecule drug discovery programmes, many of which are ongoing or unpublished. 

Innovation is also a key passion of mine as evidenced being a key player in redefining the CNS drug discovery lead optimisation process:

• 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

I have a number of investigative projects currently ongoing that could have significant impact on the drug discovery pathway for the diseases that we focus on or more broadly.

I have over 32 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. As a DMPK leader, with particular expertise in CNS and anti-infective drug discovery, I have achieved a considerable track record of success, playing a significant part in 11 compounds entering pre-clinical development, 8 of which have entered clinical trials. 

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 build a DMPK group from the ground up.  I now have a team of 20 DMPK scientists with extensive Biopharma DMPK experience. I have also led the development within the DDU of key rodent models of disease for the kinetoplastid diseases; Human African trypanosomiasis, Visceral Leishmaniasis and Chagas’ disease.  My group has all the skills and tools necessary to ensure that only those molecules with appropriate developability to deliver the required target product profile will progress toward candidate nomination. 

I have also been on the DDU management team since joining the DDU in 2008 and I am also on the board for our Wellcome Centre that was awarded in 2017. I have helped grow the DDU to over 130 scientists delivering a fully integrated drug discovery engine embedded in Academia. I have brought in, and continue to bring in, substantial funding to the DDU from sources such as Wellcome and the Bill and Melinda Gates Foundation and currently I am a lead investigator on active grants with income >£16M/ year. I have strong fully integrated collaborations with a number of major Pharma companies.