Elrig Drug Discovery conference Drug Discovery Elrig Drug Discovery conference 2018 Steven Zimmer CEO

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  • Drug Discovery: Reductionism v Complexity

    Elrig Drug Discovery conference 2018

    Steven Zimmer

    CEO

    MitoDys and EpiCombi Therapeutics

  • Brief Bio

    • Biochemist/Molecular Biologist

    • Long career as an Analyst, Investment Banker, Portfolio Manager

    • Visiting researcher SGC, Oxford University

    • Rare Disease Consortium Oxford

    • Biotech Entrepreneur

    • Protein Sciences (sold to Sanofi 2017)

    • MitoDys Therapeutics

    • EpiCombi Therapeutics

    • Others!

  • Why are we here?

    Alleviate suffering and reduce mortality….right?

    Have we really been successful?

    To a degree we have…but…

    All of the low hanging fruit has been picked!

    Left with…highly complex intractable multi-factorial diseases

    Cause significant morbidity and early mortality

    However….Drug discovery is stuck

  • Why is drug discovery stuck?

    Absolutely obsessed with targets

    …pathologically so!!

    Reduction to a target is the be all end all

    When it does not work (96% of the time!!)…

    Supposedly…Need better targets

    And on and on and on and on…..

    Is this really the way that biology works?

  • This is what I learned!

    TCA/Kreb Cycle

    ACTUALLY…

  • Reality Check!!!

  • The Internet

  • Ecological Network

  • Biological Networks

    Built to be robust

    Fault-Tolerant

    Modular and interconnected

    Are so through:

    • Ability to Adapt

    • Crosstalk and feedback loops

    • Redundancies/Alternate functional paths

    Single Target???????

  • Biology: Interaction network of modules.

    Luo F et al. Bioinformatics 2007;23:207-214

  • Disease: Multi- factorial complexity

    • It gets worse!!!

    • Breakdown of cellular functionality/failure of multiple systems

    • Multi cell-type dysfunction

    • Genes

    • Immune system interactions

    • Epigenetic drivers

    • Multiple RNA types

    • Post-translational modifications

    • ….etc…etc….etc.

    • In other words….its a….!

  • To make things even worse…

    Drug promiscuity

  • How to harness this…

    To deal with that?

    Hierarchical Clustering

    Gluccocorticoids

    Benzodiazepenes

    Estrogenics

    MAO inhibitors

    Opiates

    Anticholinergics

    Beta blockers

    Antipsychotics,

    SSRIs,Tricyclics

    etc.

    NSAIDs

    I1 5

    I1 0

    I0 4

    E 3 2

    E 1 2

    E 0 4

    I1 3

    R 2 6

    R 9 1

    R 6 2

    E 0 9

    I1 2

    E 2 5

    I0 8

    R 5 5

    I1 1

    E 1 8

    E 2 2

    E 3 1

    I0 2

    R 1 6

    I0 7

    R 8 2

    R 1 2

    E 1 4

    E 2 7

    I0 5

    I1 4

    R 2 4

    E 0 7

    E 1 1

    R 7 5

    R 2 9

    R 3 8

    R 4 7

    R 9 0

    I0 1

    R 1 5

    R 0 1

    R 6 3

    R 8 9

    R 2 8

    R 5 1

    R 8 4

    T 0 5

    T 0 4

    R 1 7

    R 6 0

    R 2 2

    R 4 3

    R 1 9

    R 2 7

    R 3 9

    R 1 8

    R 2 1

    R 8 8

    R 4 4

    I0 3

    R 1 3

    I0 6

    R 7 8

    R 7 2

    R 1 4

    R 0 2

    T 0 2

    Hierarchical Clustering

    Gluccocorticoids

    Benzodiazepenes

    Estrogenics

    MAO inhibitors

    Opiates

    Anticholinergics

    Beta blockers

    Antipsychotics,

    SSRIs,Tricyclics

    etc.

    NSAIDs

    I1 5

    I1 0

    I0 4

    E 3 2

    E 1 2

    E 0 4

    I1 3

    R 2 6

    R 9 1

    R 6 2

    E 0 9

    I1 2

    E 2 5

    I0 8

    R 5 5

    I1 1

    E 1 8

    E 2 2

    E 3 1

    I0 2

    R 1 6

    I0 7

    R 8 2

    R 1 2

    E 1 4

    E 2 7

    I0 5

    I1 4

    R 2 4

    E 0 7

    E 1 1

    R 7 5

    R 2 9

    R 3 8

    R 4 7

    R 9 0

    I0 1

    R 1 5

    R 0 1

    R 6 3

    R 8 9

    R 2 8

    R 5 1

    R 8 4

    T 0 5

    T 0 4

    R 1 7

    R 6 0

    R 2 2

    R 4 3

    R 1 9

    R 2 7

    R 3 9

    R 1 8

    R 2 1

    R 8 8

    R 4 4

    I0 3

    R 1 3

    I0 6

    R 7 8

    R 7 2

    R 1 4

    R 0 2

    T 0 2

    Biological Complexity Networks

    Fault Tolerance Redundancies

    Plasticity...

    Drug Promiscuity

    Targeted??? Never!

    Proteins

    D ru

    gs

    Single Target??? Where?

    Biology & Drugs: Complexity & Single Targets

    Drug promiscuity

  • What to do????

    1 Tie a cement block to

    your foot and jump into the dock water outside

    or… Commit Seppuku in front

    of the Excel Centre

    2 Take one of the happy

    pills I left in a box outside the hall

    This is a drug discovery conference after all!

    3 Listen to what I have to

    say next…

  • Solutions:Data

    • A Galaxy of Data!!!

    • Omics of all sorts (Genomic, Proteomic, Methylomic, Metabolomic….)

    • RNA

    • Sequencing/Genetic

    • Clinical

    • Chemical

    • Chemical Biological

    • Pharmacological

    • Genetics

    • And so on…

  • Solutions: Analytics

    Accessible Public Datasets

    Inaccessible Pharma/Biotech data

    Plethora of Analytical tools

    Ability to create new ones

    Invent new ways of combining data

  • How do we apply this to Drug Discovery?

    Think Differently

    • System

    • Biological mechanisms

    • Modification of phenotype

    • How to dissect disease biology and link it to pharmacology and drugs?

  • How do I think? Signatures Omics

    and chemical

    data

    Using:

    •Current pharmacopei a,

    •Failed/discon tinued drugs

    •High quality chemical probes

    Generate prototype

    drugs (single or

    combination) to test

    Use Machine Learning to train

    this data to predict patterns

    Identify further

    prototype drugs to

    test

  • Polypharmacology…what a mess…or…

    • Phenotypic change and Biomarkers identified

    • Biological tools to manipulate

    • Identify active components

    • Use to construct single compounds with dual activity or

    • Formulated combinations with known compounds

    Deconvolution to the

    essentials

  • Lessons to learn

    Remember….this is about patients!!!

    Change must come to achieve greater productivity and success

    Emerging paradigm: network and systems pharmacology

    Extraordinarily disruptive in Pharma/Biotech context

    The whole system is geared to oppose this

    While it is easier to simplify things…it generates costly errors

    Prevailing Reductionist paradigm is broken

    Paul Ehrlich’s Magic Bullit is not relevant anymore

    We know so much more than he did!!!

  • Conclusions

    Much more to say

    Not about dissing medicinal chemists and conventional pharmacology

    Provoke thought and discussion

    Knowledge and Tools

    Use them for the right purpose

    Heart wrenching stories of unnecessary suffering out there

    Rational solutions

  • THANK YOU!!! Steven.zimmer@epicombi.com

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