Drug Repurposing
John P. OveringtonStratified Medical
@johnpoverington
~5,000 ‘treated’ diseases~14,400 diseases (~7,000 rare diseases) ~400 drug targets
~19,000 genes in human genome
~1,500 drugs~1,000,000,000,000,000,000,000 drug-like molecules
Drug
TargetDisease
Stratified Medical – Deep Learning in Drug Discovery
T. Oprea & J.P. Overington (2015) ‘Computational and Practical Aspects of Drug Repositioning’ Drug Repositioning, Repurposing and Reuse, 1, 28-35 DOI:10.1089/drrr.2014.0009
also published in
ASSAY and Drug Development Technologies (2015) 13 299-306 DOI:10.1089/adt.2015.29011.tiodrrr PMID:26241209
DREL
Drug Repurposing
• Drug Repurposing
– Finding a new clinical use for an approved drug
• Drug Rescue
– Finding a clinical use for a stalled clinical development stage compound
• Phase 2 or beyond – established PK and tolerability, maybe safety and usually a known chemical structure
Drug Repurposing
Some Will Pay For What Others Pay To Avoid…
Bimatoprost
Lumigan TM Latisse TM
What Drugs Are Already Used For
• There is no consistent description of disease and drug linkage– Several classification schemes exist but it is in the
physicians, regulators and manufacturers interest to stay silent on the precise diseases
– The Drug ‘Label’ is the best guide to allowed use– The best useful scheme though is probably the WHO
ATC
• Side effects are usually ‘negative’ ones– Manufacturers need to be very careful about off-label
promotion
The WHO ATC
• ATC – Anatomical Therapeutic Chemical Classification
– Updates for new drugs and drugs in registration phase
– Contains combinations, and some odd things
– Often coupled with DDD
• DDD is the defined daily dose – typical daily dose for an adult being treated with the drug
ATC Level 1
First level• The first level of the code indicates the anatomical main group and consists of one letter.
Code ContentsA Alimentary tract and metabolismB Blood and blood forming organsC Cardiovascular systemD DermatologicalsG Genito-urinary system and sex hormonesH Systemic hormonal preparations, excluding sex hormones and insulinsJ Antiinfectives for systemic useL Antineoplastic and immunomodulating agentsM Musculo-skeletal systemN Nervous systemP Antiparasitic products, insecticides and repellentsR Respiratory systemS Sensory organsV Various
ATC Levels 2 to 5
Second level• The second level of the code indicates the therapeutic main group and consists of two digits.• Example: C03 Diuretics
Third level• The third level of the code indicates the therapeutic/pharmacological subgroup and consists of one
letter.• Example: C03C High-ceiling diuretics
Fourth level• The fourth level of the code indicates the chemical/therapeutic/pharmacological subgroup and
consists of one letter.• Example: C03CA Sulfonamides
Fifth level• The fifth level of the code indicates the chemical substance and consists of two digits.• Example: C03CA01 Furosemide
Selection of Drugs for Repositioning
• Product profile can/should be used to restrict set– E.g. Known oral dosing, no safety warnings, low
DDI potential, non-irreversible, no controlled substances, no cytotoxics…..
• Use a filtered USAN/INN set– Annotated with a few in silico models
– E.g. HERG, BBB
– ~3,000 ‘high priority’ compounds
Prodrugs Are Problematic
Other Structural Complexities• Tautomers
• Epimerization
• Covalent/reactive
• Active metabolites
• Hydration
• Enumeration of stereoisomers…
Protein Kinases
• Built dataset of clinical stage small molecule protein kinase inhibitors
• 33 approved (3 Japan only, 1 China only)
• 488 in total – 2-D structures for 68%– many errors in structure
assignment in literature– Patents– (claimed) Targets
• Implemented a systems pharmacology pipeline to investigate repositioning and resistance profiling
Drug Repurposing
• On Target – Finding new uses of a drug acting through the originally
known target– Literature, omics experiments…..– Positive feature is that it is likely to be compatible with
dosing of original drug
• Off Target– Finding new uses of a drug acting through a novel or
unanticipated target– Docking, fingerprint methods,….– Drug was not originally optimised for that target, so need
to be watchful of dosing
Drug Repurposing
• Simplest case is to take a library of drugs and screen them in a model assay
– We will look at two papers that did just this, both working on neglected diseases
Drug Action
Master headline05.11.20152
1
Pla
sma
con
cen
trat
ion
Cp
(mg
/L)
Time (hr)
XC50 ‘efficacy’ target
100
75
50
25
% effect
Acute ADRs Primarily Cmax Linked
Master headline05.11.20152
2
Pla
sma
con
cen
trat
ion
Cp
(mg
/L)
Time (hr)
XC50 ‘off’ target
• Cmax can vary greatly due to drug dose and a wide range of environmental and geneticfactors• Occurrence and duration of side-
effects appears stochastic
• Examples• QT prolongation/hERG effects for
cisapride – potentially fatal• Blue vision side effect for sildenafil –
an inconvenience
100
75
50
25
% effect
Pharmacology Spectrum of a Drug
Master headline05.11.20152
3
Pla
sma
con
cen
trat
ion
Cp
(mg
/L)
Time (hr)
XC50 ‘efficacy’ target
XC50 ‘off’ target
XC50 ADR target
As concentration increases, an ever larger number of targets are affected
⇥ Higher dosing - more pharmacology, both positive and negative
Drug Repurposing
• ‘On Target’ – Finding new uses of a drug acting through the originally known
target– Literature, transcriptomics/GWAS experiments…..– Positive feature is that it is likely to be compatible with dosing of
original drug– Big exception of ‘privileged’ compartments – occular, brain
• ‘Off Target’– Finding new uses of a drug acting through a novel or
unanticipated target– Docking, fingerprint methods,….– Drug was not originally optimized for that target, so need to be
very critical of dosing
Off Target Effects ‘Not Optimised’
Master headline05.11.20152
5
Pla
sma
con
cen
trat
ion
Cp
(mg
/L)
Time (hr)
XC50 ‘off’ target
• Affinity for novel beneficial target is likely to be lower than for ‘on-target’
• Almost certainly non-optimal dosage/pharmacokinetics for new target• Dependent on disease
How to Find Out About Drugs
• The Prescribing Information (PI)/Summary of Product Characteristics (SPC) is a good place to start
– Let’s look at one…..
• Wikipedia is good – but confirm things
– Abiraterone, Lemborexant,….
Drug Repurposing Practical
John Overington – Stratified Medical
3rd November 2015
Product Profile
• The pharmaceutical requirements of a drug– Delivery route
• Oral, parenteral, topical, inhaled….
– Drug Drug interactions– Differentiation from current therapies
• Safety, Cost, Efficacy
– Dosing frequency• Every eight hours, every day, every week, every month
– Cost of goods– Risk of Misuse/Controlled substances– Tolerable side effects– Safety in pregnant/breastfeeding populations– Dose adjustment in pediatric patients– Monitoring – specialist use, liver function tests,…– …
Task
• 5 minutes - As a class: Develop a prototypical product profile for a novel antimalarial– Consider dosing, safety, cost of goods, patient
population….
• 30 minutes - As small teams: Examine hits from the Yuan paper– Classify dosing, safety, and approval status
– Triage drugs to most likely repurposing candidates
• 10 minutes – As a class: Select realistic drug repositioning prospects
What The Results Should Look Like
Aspirin would be…..
Some Homework
