Andrew Marsh

Department of Chemistry

University of Warwick

go.warwick.ac.uk/marshgroup Twitter @marshgroup

27 Nov 2014, School of Engineering, University of Warwick

Personalized medicine: opportunities for chemistry

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)

“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 SingerTherapeutic Delivery, 2010, 1, 651-665

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

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

Genomic testing

‘Genomics and Drug Response’ L Wang, H L McLeod, R M Weinshilboum New England J. Med. 2011, 364, 1144

• 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”

CYP2D6

Clinical effects Disease-relevant networks ADRs

QT prolongation(HERG channel inhibition)

Oxidation by CYP2D6 to

Graphic inspired by Pujol A, Mosca R, Farres J, Aloy P. ‘Unveiling the role of network and systems biology in drug discovery’ Trends Pharmacol. Sci. 2010, 31, 115–123.

Network pharmacology view of Asthma

Network pharmacology: The next paradigm in drug discovery. Hopkins A I, Nat Chem Biol 2008, 4, 682-690

Edges: compounds active against both targetsYellow, orange, salmon – GPCRs Blue – Ion channelsBrown – nuclear hormone receptorsPurple – phosphodiesterasesPink – protein kinases

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

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

Monotherapies

around 1979 > USD 1bn in sales p.a.

Classically, histamine H2 receptor antagonists, e.g. cimetidine are characterised as ‘single target’

Polypharmacology – Foe or Friend? J.-U. Peters J. Med. Chem. 2013, doi:10.1021/jm400856t

PolypharmacologySingle entity, multi-targeted therapeutic agent: imatinib. Additional targets & indications discovered post-market

BCR-abl tyrosine kinase c-Kit receptor tyrosine kinase lymphocyte tyrosine kinase

Polypharmacology: Many effective medicines discovered serendipitously, or from phenotypic

screens

Leading to a need for …

Designing Multi-Target Drugs J C Harris, J R Morphy (Eds.) 2012

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 be found through ChEMBL or ChemBioNavigator

… data linking therapeutics and targets

Affinity chromatography of cell lysateChem Soc Rev 2008, 37, 1347

Revealing hidden phenotypes: Protein complementation assaysNCB, 2006, 2, 329

Shared side-effects

Science, 2008, 321, 263

Knock-out organismsRNAi knock-down

Display librariesChem. Biol. 1999, 6, 707-716

Functional group tag and SAR studyJACS 2007, 129, 12222

PhotoimmobilisationACIEE, 2003, 42, 5584

Small molecule microarraysChem. Biol. 2006, 13, 493

Magic Tag®

Chem Commun 2007, 2808ChemMedChem 2008, 3, 742Chem Commun 2013, 10.1039/c3cc44647f

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

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

Pharmacology of molecular- and tissue-targeted drug action

‘Magic Bullet’

(theory)

Tissue-targeted systems

pharmacology

‘Magic blunderbuss

’(current practice)

Polypharmacology

single multiple

sing

lem

ultip

le

molecular target

tis

sue

tar

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t

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

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 TargetsBindingdB http://www.bindingdb.org/bind/index.jsp >180 000 3.673ChEBI http://www.ebi.ac.uk/chebi/init.do >28 000ChEMBL https://www.ebi.ac.uk/chembldb/ >1 million >8.800ChemProt http://www.cbs.dtu.dk/services/ChemProt/ >700 000 >30<comma>000ChemSpider http://www.chemspider.com/ >26 million NoneDRAR-CPI http://cpi.bio-x.cn/drar/Drug Adverse Reaction Target Database http://xin.cz3.nus.edu.sg/group/drt/dart.asp 1080 236DrugBank http://www.drugbank.ca/ 6.711 4.227iPHACE http://cgl.imim.es/iphace/ 739 181MATADOR http://matador.embl.de/ 775PDSPKi http://pdsp.med.unc.edu/kidb.phpPharmGKB http://www.pharmgkb.org/Potential Drug Target Database (PDTD) http://www.dddc.ac.cn/pdtd/ - 841PROCOGNATE http://www.ebi.ac.uk/thorntonsrv/databases/procognate/PROMISCUOUS http://bioinformatics.charite.de/promiscuous/ >25 000PubChem http://pubchem.ncbi.nlm.nih.gov/ >31 million >1.600 assaysPubChem promiscuity http://chemutils.florida.scripps.edu/pcpromiscuitySePreSA http://sepresa.bio-x.cn/SIDER2 http://sideeffects.embl.de/ 996 4.199SuperTarget http://bioinformatics.charite.de/supertarget/ 195 770 6219TarFisDock http://www.dddc.ac.cn/tarfisdockTDR Targets http://tdrtargets.org 825 814Therapeutic Target Database (TTD) http://bidd.nus.edu.sg/group/ttd/ 17 816 2.015Toxin, toxin-target database (T3DB) http://www.t3db.org/ 2900 1.3Transporter Classification DataBase (TCDB) http://tcdb.org/

atorvastatin rosuvastatin

ABCB1

ABCC1 ABCC1

ABCC4 ABCC4

ABCC5

ABCG2 ABCG2

SLCO1A2 SLCO1A2

SLCO1B1 SLCO1B1

SLCO1B3

Known drug - transporter interactions for two statins

DB Kell, PD Dobson, E Bilsland, SG Oliver Drug. Disc. Today 2013, 18, 218

See also UCSF-FDA Transportal & Human Transporter Database

130 Defined Daily Dose statins per 1000 population UK[oecd.org Health at a Glance 2013]

• Which relevant transporters are present in your cell and tissue targets?

Modifiable factors and the individual genome

Clinical assessment incorporating a personal genome: Ashley EA, Butte AJ, Wheeler MT et al. Lancet 2010, 375, 1525-1535

Much genomic variation leads to small individual (odds ratio 1.1-1.3) benefits or risks

Modifiable factors

Disease risk:Text size proportional to risk probability

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

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