Talk delivered at Warwick Biomedical Engineering Seminar series 27 November 2014. Develops a theme emerging from a review in 2010: J Watkins, A Marsh, P C Taylor, D R J Singer Therapeutic Delivery, 2010, 1, 651-665 "Continued adherence to a single-drug single-target paradigm will limit the ability of chemists to contribute to advances in personalized medicine, whether they be in discovery or delivery"

1. Personalized medicine:
opportunities for chemistry
Andrew Marsh
Department of Chemistry
University of Warwick
27 Nov 2014, School of Engineering, University of Warwick
go.warwick.ac.uk/marshgroup Twitter @marshgroup

2. Personalized medicine
“...tailoring of medical treatment to the individual
characteristics of each patient. It does not
literally mean the creation of drugs or medical
devices that are unique to a patient, but rather
the ability to classify individuals into
subpopulations that differ in their susceptibility to
a particular disease or their response to a
specific treatment.”
Marburger JH (III); Kvamme EF, Council of Advisors on Science: Priorities for
personalized medicine. (2008)

3. “Continued adherence to a single-drug single-target
paradigm will limit the ability of chemists
to contribute to advances in personalized
medicine, whether they be in discovery or
delivery”
J Watkins, A Marsh, P C Taylor, D R J Singer
Therapeutic Delivery, 2010, 1, 651-665

4. Human epidermal growth factor receptor 2
• ERRB2 encodes human epidermal growth factor
receptor 2 (HER2) and is over-expressed in 20-
30% of patients with breast cancer (‘HER2+’)
• Monoclonal antibody therapy trastuzumab is only
effective in these patients
• Parallel development of biopsy
companion diagnostic test
• Cardiac toxicity (2% patients)
HER2/Neu complex with trastuzumab: 1N8Z.pdb

5. Adverse drug reactions: ADRs
• 7% of urgent admissions to UK hospitals due to
ADRs at annual cost of GBP466M (2004)
• 72% of which were avoidable
• Many due to prescription of multiple therapeutics
(“polypharmacy”, which has implications for new
therapeutic approaches)
Adverse drug reactions as cause of admission to hospital: Prospective
analysis of 18 820 patients. Pirmohamed M, James S, Meakin S et al.
British Med. J. 2004, 329, 15-19

6. Genomic testing
• CYP2C9, VKORC1 SNP polymorphisms account for 30-40% in variation of
warfarin anticoagulant dose required.
• Genotype guided prescribing reduced all cause hospital admissions by up to 10%
• HLA B*1502 allele testing in 5000 Taiwanese before carbamazepine therapy for
epilepsy revealed 8% at risk of Stevens-Johnson syndrome or toxic epidermal
necrosis.
• No cases of those ADRs were recorded as a result of genome-guided prescribing.
“The use of genotyping to inform clinical decisions about drug use is not
widely practiced”
‘Genomics and Drug Response’ L Wang, H L McLeod, R M Weinshilboum New
England J. Med. 2011, 364, 1144

7. CYP2D6
Clinical effects Disease-relevant networks ADRs
P
R
Q
S
T
QT Interval
QT prolongation
(HERG channel
inhibition)
Protein 4
Protein 3
Protein 2
Protein 1
Oxidation by CYP2D6 to
Graphic inspired by Pujol A, Mosca R, Farrés J, Aloy P. ‘Unveiling
the role of network and systems biology in drug discovery’ Trends
Pharmacol. Sci. 2010, 31, 115–123.

8. Network pharmacology view of Asthma
Edges: compounds active against both targets
Yellow, orange, salmon – GPCRs
Blue – Ion channels
Brown – nuclear hormone receptors
Purple – phosphodiesterases
Pink – protein kinases
Network pharmacology: The next paradigm in drug discovery. Hopkins A I, Nat Chem Biol 2008, 4, 682-690

9. How can network pharmacology help to
personalize medicines?
• Challenge: linking network pharmacology and
contingent pathways with personalized medicine
• Opportunity: recognise that most therapeutics
exhibit polypharmacology

10. Terminology and definitions
• Monotherapy
– Classical ‘single target – single disease’ drug
• Polypharmacology
– Interaction of a small drug molecule with multiple
targets
• Polypharmacy
– Prescription of multiple drugs
• Pharmacogenomics
– Study of inter-individual drug response
(efficacy/toxicity) based on genetic variation

11. Monotherapies
Classically, histamine H2 receptor antagonists,
e.g. cimetidine are characterised as ‘single
target’
Monotherapies:
one drug – one target – one disease
N
N
H
CH3
S
cimetidine
N
H
N
NH
CH3
CN
around 1979 > USD 1bn in sales p.a.
Polypharmacology – Foe or Friend? J.-U. Peters J. Med. Chem. 2013,
doi:10.1021/jm400856t

12. Polypharmacology
Single entity, multi-targeted therapeutic agent: imatinib.
Additional targets & indications discovered post-market
N
N
N
H
N
HN
O
CH3
N
N
imatinib
BCR-abl tyrosine kinase c-Kit receptor tyrosine kinase lymphocyte tyrosine kinase

13. Polypharmacology: Many effective medicines
discovered serendipitously, or from phenotypic
screens
Redrawn from M Shahid, G B Walker, S H Zou, E H F Wong J. Psychopharmacol. 2009, 23, 65 - 73
J R Morphy Drug Discovery Today, 2004, 9, 641 - 651 Polypharmacology data can
Designing Multi-Target Drugs J C Harris, J R Morphy (Eds.) 2012
Leading to a need for …
be found through ChEMBL or
ChemBioNavigator

14. … data linking therapeutics and targets
O
O OH
H
O
O
CH3
OH O
O
Ph
O
O
O
H3C
O
Ph
NH
OH
O
Ph
Affinity chromatography of cell lysate
Chem Soc Rev 2008, 37, 1347
Revealing hidden phenotypes:
Protein complementation assays
NCB, 2006, 2, 329
Shared side-effects
Science, 2008, 321, 263
Knock-out organisms
RNAi knock-down
Magic Tag®
Chem Commun 2007, 2808
ChemMedChem 2008, 3, 742
Chem Commun 2013, 10.1039/c3cc44647f
Display libraries
Chem. Biol. 1999, 6, 707-716
Functional group tag and SAR study
JACS 2007, 129, 12222
Photoimmobilisation
ACIEE, 2003, 42, 5584
Small molecule microarrays
Chem. Biol. 2006, 13, 493

15. Polypharmacy
Mixtures of monotherapies: e.g. co-formulated anti-retrovirals
A challenge for chemists, pharmacists and clinicians
For discussion of pharmacogenetic and pharmacoecologic factors in antiviral therapy e.g. hepatitis C
see: R Pavlos, E J Phillips Pharmacogenomics and Personalized Medicine 2012, 5, 1-17

16. How to integrate pharmacokinetic (PK) -
pharmacodynamic (PD) knowledge with
personalized formulation and delivery?
• Fixed dose combinations for known population heterogeneities
• Polymers: time release technology; stabilization of biologicals
• Nanostructures: design and selection of desired properties such
as solubility; intracellular targeting?
• Selective delivery – not magic bullets, but better understanding
of cell and tissue properties; how these change with disease
http://www.proteinatlas.org

17. Pharmacology of molecular- and tissue-targeted
drug action
single multiple
‘Magic Bullet’ (theory)
Tissue-targeted systems
pharmacology
‘Magic blunderbuss’
(current practice)
Polypharmacology
multiple single
molecular target
tissue target
D B Kell, S G Oliver “How drugs get into cells: tested and testable predictions to help discriminate
between transporter-mediated uptake and lipoidal bilayer diffusion”, Frontiers Pharmacol. 2014, doi:
10.3389/fphar.2014.00231

18. Genomics and transporter pharmacology
“The promiscuous binding of pharmaceutical drugs and their transporter-mediated
uptake into cells: what we (need to) know and how we can do so”
DB Kell, PD Dobson, E Bilsland, SG Oliver Drug. Disc. Today 2013, 18, 218.
Database URL Drugs Targets
BindingdB http://www.bindingdb.org/bind/index.jsp >180 000 3.673
ChEBI http://www.ebi.ac.uk/chebi/init.do >28 000
ChEMBL https://www.ebi.ac.uk/chembldb/ >1 million >8.800
ChemProt http://www.cbs.dtu.dk/services/ChemProt/ >700 000 >30<comma>000
ChemSpider http://www.chemspider.com/ >26 million None
DRAR-CPI http://cpi.bio-x.cn/drar/
Drug Adverse Reaction Target Database http://xin.cz3.nus.edu.sg/group/drt/dart.asp 1080 236
DrugBank http://www.drugbank.ca/ 6.711 4.227
iPHACE http://cgl.imim.es/iphace/ 739 181
MATADOR http://matador.embl.de/ 775
PDSPKi http://pdsp.med.unc.edu/kidb.php
PharmGKB http://www.pharmgkb.org/
Potential Drug Target Database (PDTD) http://www.dddc.ac.cn/pdtd/ - 841
PROCOGNATE http://www.ebi.ac.uk/thorntonsrv/databases/procognate/
PROMISCUOUS http://bioinformatics.charite.de/promiscuous/ >25 000
PubChem http://pubchem.ncbi.nlm.nih.gov/ >31 million >1.600 assays
PubChem promiscuity http://chemutils.florida.scripps.edu/pcpromiscuity
SePreSA http://sepresa.bio-x.cn/
SIDER2 http://sideeffects.embl.de/ 996 4.199
SuperTarget http://bioinformatics.charite.de/supertarget/ 195 770 6219
TarFisDock http://www.dddc.ac.cn/tarfisdock
TDR Targets http://tdrtargets.org 825 814
Therapeutic Target Database (TTD) http://bidd.nus.edu.sg/group/ttd/ 17 816 2.015
Toxin, toxin-target database (T3DB) http://www.t3db.org/ 2900 1.3
Transporter Classification DataBase (TCDB) http://tcdb.org/

19. Known drug - transporter interactions for two statins
atorvastatin rosuvastatin
ABCB1
ABCC1 ABCC1
ABCC4 ABCC4
ABCC5
ABCG2 ABCG2
SLCO1A2 SLCO1A2
SLCO1B1 SLCO1B1
SLCO1B3
See also UCSF-FDA Transportal & Human Transporter Database
DB Kell, PD Dobson, E Bilsland, SG Oliver Drug. Disc. Today 2013, 18, 218
• Which relevant transporters are present in your cell and tissue targets?
130 Defined Daily Dose statins per 1000 population UK
[oecd.org Health at a Glance 2013]

20. Modifiable factors and the individual genome
Modifiable factors
Much genomic variation leads to small individual (odds ratio 1.1-1.3) benefits or risks
Clinical assessment incorporating a personal genome: Ashley EA, Butte AJ,
Wheeler MT et al. Lancet 2010, 375, 1525-1535
Disease risk:
Text size
proportional to
risk probability

21. What do we need in order to achieve
personalized, multi-target therapeutics?
• Recognise that therapeutics act on targets within networks,
rather than at the individual gene level, leading to both
beneficial and adverse actions
• Improved understanding of quantitative PK-PD data; use of
network data in building models
• Clinicians able to help chemists and engineers understand the
problems faced by patients (and by clinicians in treating them!)
• Need for a greater interdisciplinary approach to innovate
solutions

22. Acknowledgements
• Dr Paul C Taylor, Department of Chemistry
• Kate Casey-Green, Department of Chemistry
• John Watkins, Dept of Chemistry; Warwick Medical School
• Professor Donald R J Singer, Warwick Medical School
Funding
• EPSRC
• University of Warwick