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
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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
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2
5
I0
8
R
5
5
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1
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1
8
E
2
2
E
3
1
I0
2
R
1
6
I0
7
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8
2
R
1
2
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1
4
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2
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5
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4
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1
1
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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
