drug repurposing - embl-ebi 2016-06-08آ  drug repurposing •drug repurposing –finding...

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  • Drug Repurposing

    John P. Overington Stratified 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.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

    http://en.wikipedia.org/wiki/Alimentary_tract http://en.wikipedia.org/wiki/Metabolism http://en.wikipedia.org/wiki/Blood http://en.wikipedia.org/wiki/Haematopoiesis http://en.wikipedia.org/wiki/Cardiovascular_system http://en.wikipedia.org/wiki/Dermatological http://en.wikipedia.org/wiki/Genito-urinary_system http://en.wikipedia.org/wiki/Sex_hormone http://en.wikipedia.org/wiki/ATC_code_H http://en.wikipedia.org/wiki/Hormonal http://en.wikipedia.org/wiki/Antiinfective http://en.wikipedia.org/wiki/Antineoplastic http://en.wikipedia.org/wiki/Immunomodulator http://en.wikipedia.org/wiki/Musculo-skeletal_system http://en.wikipedia.org/wiki/Nervous_system http://en.wikipedia.org/wiki/Antiparasitic http://en.wikipedia.org/wiki/Insecticide http://en.wikipedia.org/wiki/Insect_repellent http://en.wikipedia.org/wiki/Respiratory_system http://en.wikipedia.org/wiki/Sensory_organ

  • 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

    http://en.wikipedia.org/wiki/ATC_code_C03 http://en.wikipedia.org/wiki/Diuretic http://en.wikipedia.org/wiki/Sulfonamide_(medicine) http://en.wikipedia.org/wiki/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 headline05.11.2015 2

    1

    P la

    sm a

    co n

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    C p

    (m g

    /L )

    Time (hr)

    XC50 ‘efficacy’ target

    100

    75

    50

    25

    % effect

  • Acute ADRs Primarily Cmax Linked

    Master headline05.11.2015 2

    2

    P la

    sm a

    co n

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    (m g

    /L )

    Time (hr)

    XC50 ‘off’ target

    • Cmax can vary greatly due to drug dose and a wide range of environmental and genetic factors • 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 headline05.11.2015 2

    3

    P la

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    (m g

    /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 headline05.11.2015 2

    5

    P la

    sm a

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    C p

    (m g

    /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 –

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