Uploaded by DR. Ahmad Farouk

5.2.1 - drug repurposing slides

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Drug Repurposing
John P. Overington
Stratified Medical
@johnpoverington
Stratified Medical – Deep Learning in Drug
Discovery
~1,500 drugs
~1,000,000,000,000,000,000,000 drug-like molecules
Drug
Disease
~5,000 ‘treated’ diseases
~14,400 diseases (~7,000 rare diseases)
Target
~400 drug targets
~19,000 genes in human genome
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.tio
drrr 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 Contents
A
Alimentary tract and metabolism
B
Blood and blood forming organs
C
Cardiovascular system
D
Dermatologicals
G
Genito-urinary system and sex hormones
H
Systemic hormonal preparations, excluding sex hormones and insulins
J
Antiinfectives for systemic use
L
Antineoplastic and immunomodulating agents
M
Musculo-skeletal system
N
Nervous system
P
Antiparasitic products, insecticides and repellents
R
Respiratory system
S
Sensory organs
V
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
Plasma concentration Cp (mg/L)
Drug Action
% effect
100
75
XC50 ‘efficacy’ target
50
25
2
1
05.11.2015
Master headline
Time (hr)
Plasma concentration Cp (mg/L)
Acute ADRs Primarily Cmax Linked
• Cmax can vary greatly due to drug dose and
a wide range of environmental and genetic
factors
• Occurrence and duration of sideeffects appears stochastic
XC50 ‘off’ target
• Examples
• QT prolongation/hERG effects for
cisapride – potentially fatal
• Blue vision side effect for sildenafil –
an inconvenience
% effect
100
75
50
25
2
2
05.11.2015
Master headline
Time (hr)
Pharmacology Spectrum of a Drug
Plasma concentration Cp (mg/L)
XC50 ADR target
2
3
05.11.2015
As concentration increases,
an ever larger number of
targets are affected
XC50 ‘off’ target
⇥ Higher dosing - more
pharmacology, both positive and
negative
XC50 ‘efficacy’ target
Master headline
Time (hr)
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’
Plasma concentration Cp (mg/L)
• 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
2
5
05.11.2015
XC50 ‘off’ target
Master headline
Time (hr)
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
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