University of Dundee

Professor Kevin Read

Drug discovery, lead optimisation and preclinical development
Position: 
Professor of Quantitative Pharmacology and Head of Drug Metabolism and Pharmacokinetics
Address: 
School of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 388688, int ext 88688
Email: 

Research

The Drug Discovery Unit (DDU) (est. 2006) within the College of Life Sciences at Dundee was created to respond to a lack of capacity in the UK for early stage drug discovery in the academic sector. The DDU’s aim is to translate basic science into lead compounds to validate putative drug targets, to use as tools to investigate disease pathways and, when appropriate, advance to pre-clinical drug candidates for multiple diseases, e.g. visceral leishmaniasis or malaria. The DDU works to Biotech style philosophy and standards incorporating dynamic, goal driven project management based on Target Product Profiles and Compound Selection Criteria. The DDU is a fully operational and integrated drug discovery team, which is rare within UK universities, with the full range of disciplines, including compound management, screening, molecular pharmacology/enzymology, medicinal chemistry, computational chemistry, DMPK and disease model capabilities, required to produce novel hit and lead candidates.

Our funding for drug discovery lead optimisation through to preclinical development comes from a number of sources.  The drug discovery for tropical diseases initiative was a programme to discover high quality drug candidates, principally for human African trypanosomiasis. The initiative was funded by the Wellcome Trust, with a budget of £8.1m over five years from 2006 to 2011. A second programme to work on kinetoplastid diseases (Leishmaniasis and Chagas’ disease as priority) in collaboration with GlaxoSmithKline’s Kinetoplastid Diseases DPU, Tres Cantos, Spain, was funded by the Wellcome Trust in 2011 (£8.6m over 5 years).

In addition, we have been funded by the medicines for malaria venture (MMV) to discover drug candidates for malaria; and we are funded by the Foundation for NIH to discover leads for tuberculosis (TB) within the HIT-TB consortium; and to carry out Lead Optimisation for Diseases of the Developing World within a programme supported jointly by the Bill and Melinda Gates Foundation and the Wellcome Trust. We also opportunistically look to re-purpose lead compounds, where possible, into animal health and are funded by GALVmed to deliver development candidates for African animal trypanosomiasis.

My background is in drug metabolism and pharmacokinetics (DMPK), with extensive experience of early phase drug discovery, lead optimisation project leadership and preclinical development gained from over 25 years in the pharmaceutical industry.  My passion is to successfully drive lead optimisation forward, working closely with the medicinal chemists to deliver high quality candidate molecules for entry into formal preclinical development. My group collectively has over 140 years of Biopharma DMPK experience and 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 through lead optimisation.

A robust preclinical development candidate will have a balance of good potency, safety and DMPK properties. These compound characteristics should therefore be optimised as early as possible in the drug discovery process so that cycle times and progression to humans is as uneventful as possible.

My group has implemented industry standard assays coupled with state of the art UPLCMSMS technology for supporting all hit to lead and lead optimisation programmes within the DDU. Our capabilities include in silico absorption, distribution, metabolism and excretion (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 optimisation process.

Our available in vitro assays include assessment of measured physicochemical properties such as pKa and LogP; assessment of metabolic stability (intrinsic clearance) using liver microsomes, hepatocytes or cytosol from a range of preclinical species and human; assessment of drug-drug interaction and bioactivation risk using recombinant enzymes or human liver microsomes, evaluating CYP450 inhibition, metabolism dependent inhibition, glutathione trapping and performing reaction phenotyping to give a preliminary understanding of the enzymology involved in the metabolism of a new compound; aqueous and simulated gastric fluid (SGF) solubility using nephelometry; determination of compound stability in different matrices (blood, SGF, buffer etc); and plasma protein and brain tissue binding determination using equilibrium dialysis in a 96-well format. Assessing plasma protein and brain tissue binding allows for correction to the free plasma and free brain concentration, both of which may be more meaningful indicators of the true efficacious concentration of a compound and so aid in understanding of pharmacokinetic/pharmacodynamic (PK/PD) relationships and, through calculation of theoretical receptor occupancy, enable better initial design of pharmacodynamic experiments.

Together with these in vitro assays, my group, on a routine basis, performs in vivo pharmacokinetics (PK), and brain penetration studies in rodents, usually mice. My in vivo pharmacologists have the expertise to perform serial blood sampling in mice so that a full PK profile can be obtained from a single animal thus significantly reducing animal usage. Additionally the in vivo pharmacologists can perform in vivo assessment of Pgp interaction using mdr1a deficient mice or chemical knockout; hepatic portal vein sampling in rats in order to obtain information on fraction absorbed and hepatic extraction that can aid in more rapidly identifying the key issues for poor bioavailability; and can provide PK/PD support using oral and/or a number of parenteral dose routes (i.v., s.c., i.p., i.m) as required to determine drug exposure in order to ensure optimal PD study design and build a better understanding of the PK/PD relationship within projects.

Our capability to perform metabolite identification from in vitro incubates or from biological matrices obtained following in vivo PK experiments has been enhanced through purchase of a UPLC Xevo Qtof MSMS.  This helps guide medicinal chemistry and can provide early indications of toxicity.

My group is also responsible for running the animal efficacy studies in support of all our kinetoplastid disease programmes. This allows a more nimble progression through to in vivo efficacy if a compound is identified as having appropriate pharmacokinetics to deliver efficacy at a well tolerated dose. Furthermore, with the need to rapidly validate targets in vivo, we use, when viable, HRNTM (CYP450 hepatic null) mice and/or implanted osmotic pumps in efficacy studies on those targets with poorly optimized chemistry in order to achieve and maintain prolonged efficacious free concentration of a compound in a mouse without the need for compound optimisation apriori.

Teaching

I teach drug metabolism and pharmacokinetics on the level 3 drug discovery module (BS32003) and I am the course manager for the level 4 advanced drug discovery module (BS42004).   I also host a level 4 project student each year.

Publications

Key Publications in last 5 years:

1. Watson JM, Wright S, Lucas A, Clarke KL, Viggers J, Cheetham S, Jeffrey P, Porter RA and Read KD (2009). Receptor occupancy and brain free fraction. Drug Metabolism and Disposition 37, 753-760
    
2. Read KD and Braggio S (2010). Assessing brain free fraction in early drug discovery. Expert Opin. Drug Metab. Toxicol. 6 (3), 337-344
    
3. 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. N-myristoyltransferase inhibitors as new leads to treat sleeping sickness. Nature, 2010, 464, 728-732
    
4. Sokolova A, Wyllie S, Patterson S, Oza SL, Read KD and Fairlamb AH (2010) Cross-resistance to nitro drugs and implications for treatment of human African Trypanosomiasis. Antimicrobial Agents and Chemotherapy 54(7), 2893-2900
    
5. Jones DC, Hallyburton I, Stojanovski L, Read KD, Frearson JA and Fairlamb AH (2010). Identification of a k-opioid agonist as a potent and selective lead for drug development against human African trypanosomiasis.  Biochem. Pharmacol. 80 (10), 1478-1486
    
6. Kajbaf M, Longhi R, Montanari D, Vinco F., Rigo M.,  Fontana S and Read KD (2011) A comparative study of the CYP450 inhibition potential of marketed drugs using two fluorescence based assay platforms routinely used in the  pharmaceutical industry (2011) Drug Metabolism Letters 5 (1), 30-39
    
7. Wyatt PG, Gilbert IH, Read KD and Fairlamb AH (2011). Target validation: Linking target and chemical properties to desired product profile. Current Topics in Med. Chem. 11, 1275-1283
    
8. Gunn RN, Summerfield SG, Salinas CA, Read KD, Guo Q, Searle GE, Parker CA, Jeffrey P, Laruelle M (2012). Combining PET biodistribution and equilibrium dialysis assays to assess the free brain concentration and BBB transport of CNS drugs. J. Cereb Blood Flow Metab. 32(5):874-83
    
9. Wyllie S, Patterson S, Stojanovski L, Simeons FRC, Norval S, Kime R, Read KD  and Fairlamb AH (2012). The Anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis. Science Translational Medicine, 4, 1-7
    
10.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. Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors. J. Med. Chem. 2012, 55, 140-152
    
11.Besnard J,  Ruda, GF, Setola V, Abecassis K, Rodriguiz RM, Huang XP, Norval S,  Sassano MF, Shin AI, Webster LA, Simeons FRC, Stojanovski L, Prat A, Seidah NG,  Constam DB,  Bickerton GR, Read KD, Wetsel WC, Gilbert IH and Hopkins A (2012)  Automated design of ligands to polypharmacological Profiles. Nature 492 (7428), 215-220

12.Brand S ,  Norcross NR , Thompson S ,  Harrison JR , Smith VC , Robinson DA , Torrie LS , McElroy  SP, Hallyburton I, Norval S , Scullion P , Stojanovski L , Simeons FRC , van Aalten D , Frearson JA ,Brenk R , Fairlamb AH , Ferguson MAJ , Wyatt PG , Gilbert  IH and Read KD (2014). LeadOptimization of a Pyrazole Sulfonamide Series of Trypanosoma brucei N-Myristoyltransferase Inhibitors:Identification and Evaluation of CNS Penetrant Compounds as Potential Treatments for Stage 2 HumanAfrican Trypanosomiasis.  J. Med.Chem. 57, 9855-9869
 

Impact

Kinetoplastids

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

 

  • Leading a partnership with GALVmed to repurpose HAT lead compounds as potential development candidates for African animal trypanosomiasis. 

 

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

 

  • Visceral Leishmania: Delivery of two lead series into full lead optimisation in partnership with GlaxoSmithKline.

 

  • Chagas’ disease:  In vivo proof of concept achieved for two novel series with a mode of action not CYP51 driven.  Delivery of one lead series into full lead optimisation in partnership with GlaxoSmithKline.

 

Malaria

 

Drug Discovery

  • Key player in redefining CNS drug discovery lead optimization process.