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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
ge
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
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