High-Throughput Screening: - ELRIG

35 Pages·2014·11.95 MB·English

by  Lorenz M. Mayr

04.09.14
High-Throughput Screening:
Challenges & Opportunities
8th ELRIG Drug Discovery Conference
Manchester/UK
September 2-3, 2014

Lorenz M. Mayr & Mark Wigglesworth
AstraZeneca Pharmaceuticals Ltd.
Discovery Sciences – Reagents and Assay Development
Discovery Sciences – Screening Sciences & Sample Management
High-Throughput Screening (HTS)
Presentation Outline
1

 Gartner
 Cycle

2

 Past
 HTS
 Experiences
 (AZ,
 BAY,
 GSK,
 NVS)

3

 Compound
 CollecCons

4

 Novel
 Assay
 &
 Screening
 Strategies

5

 Open
 InnovaCon
 Strategies

6

 Future
 HTS
 Technologies

7

 Summary
 &
 Outlook

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04.09.14
Gartner Cycle (‘Hype Cycle’)
The Principle
y
bilit Peak of Inflated Expectations
si
Vi
s /
n
o Plateau of Productivity
ati
ct
e
p
Ex Slope of Enlightenment
n /
o
nti Trough of Disillusionment
e
Att Technology Trigger
Time
Ref: Jackie Fenn (1995) The Microsoft System Software Hype Cycle Strikes Again
http://www.gartner.com/technology/research/methodologies/hype-cycle.jsp

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Gartner Cycle (‘Hype Cycle’)
Example 1 – Mobile Telephone
y
bilit Everyone uses a cell phone
si
Vi
s /
n
o Use of ‘smart phones’
ati
ct
e
p
Ex Smart use of cell phones
n /
o
nti Annoying use of cell phone
e
Att First cell phones
Time
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04.09.14
Gartner Cycle (‘Hype Cycle’)
Example 1 – Mobile Telephone
y
bilit Everyone uses a cell phone (2001)
si
Vi
s /
n
o Use of ‘smart phones’ (2014)
ati
ct
e
p
Ex Smart use of cell phones (2006)
n /
o
nti Annoying use of cell phone (2003)
e
Att First cell phones (1994)
Time
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Gartner Cycle (‘Hype Cycle’)
Example 2 – Internet
y
bilit Dotcom Hype
si
Vi
s /
n
o Use of ‘internet 3.0’
ati
ct
e
p
Ex Smart web applications
n /
o
nti Dotcom Burst
e
Att First internet users
Time
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3
04.09.14
Gartner Cycle (‘Hype Cycle’)
Example 2 – Internet
y
bilit Dotcom Hype (2001)
si
Vi
s /
n
o Use of ‘internet 3.0’ (2014)
ati
ct
e
p
Ex Smart web applications (2006)
n /
o
nti Dotcom Burst (2003)
e
Att First internet users (1994)
Time
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Gartner Cycle (‘Hype Cycle’)
Example 3 – High Throughput Screening (HTS)
y
bilit Everything by HTS
si
Vi
s /
n
o ‘Intelligent’ HTS
ati
ct
e
p
Ex Smart HTS/FBS/FS/VS
n /
o
nti Nothing by HTS
e
Att First screening
Time
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04.09.14
Gartner Cycle (‘Hype Cycle’)
Example 3 – High Throughput Screening (HTS)
y
bilit Everything by HTS (2001)
si
Vi
s /
n
o ‘Intelligent’ HTS (2014)
ati
ct
e
p
Ex Smart HTS/FBS/FS/VS (2006)
n /
o
nti Nothing by HTS (2003)
e
Att First screening (1994)
Time
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High-Throughput Screening (HTS)
Key Milestones
y
bilit Everything by HTS
si
Vi
s /
n
o ‘Intelligent’ HTS
ati
ct
e
p
Ex Smart HTS/FBS/FS/VS
n /
o
nti Nothing by HTS
e
Att First screening
Time
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High-Throughput Screening (HTS)
Key Milestones
low success rate of HTS: High-Content Biology/HCB;
promiscuous inhibitors, FCS-readout technologies;
uHTS factories non-tractable targets, Fluorescence-lifetime/FLT; ‘Integrated Lead
(125 x 1.5 mio cpd p.a.); non drug-like compounds; Affinity-selection MS/ASMS Discovery’:
maximum throughput; combination of
large combichem library HTS, FBS, FS, VS, PDD
assay miniaturisation phenotypic screening:
(384w -> 1536w format); primary, recombinant
automation, robotics; and stem cell screening;
recombinant cell lines mRNA transcriptomics
assay miniaturisation DNA-encoded chemical
(96w -> 384w format); libraries/DEL screening;
automation, robotics; Flow-cytometry (FACS)
non-radiometric assays; enabled screening
screening of natural 2D+, 3D & organoid-
products/extracts; outsourcing of HTS; acoustic dispensing; based screening;
microtitre plates (96w); virtual screening/VS; orthogonal hit validation; micro-physiological
radiometric assays focused screening/FS; novel assay technologies; systems (lab-on-a-chip)
fragment screening/FBS better tools/reagents
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AstraZeneca
Hit Finding Strategies
Diversity Structural Phenotypic DNA Encoded Public-Private &
Screening Biology & Drug Library Private-Private
(HTS, FS, VS) Fragments Discovery Technology Partnerships
§ Established Global § Large expertise in § Hit Discovery using § Screening of very § Hit Discovery
HTS Centre FBLG by NMR & primary / stem cell large libraries of using academic
SPR, and assays assays for finding compounds and industrial
§ Modular systems to
ensure flexibility § Dedicated team to of pathway specific (>1010 molecules) partners
perform chemistry hits § Collaboration with § Novel chemical
§ Broad set of assay § Broad range of § iPSC alliance with external partner space
technologies for all biophysical external partner § Build-in selectivity § Novel biological
types of targets technologies § Dedicated team to profiling in hit space
§ Strong capacity for § Specific fragment perform chemistry finding strategy § Synergies
cherry picking library for FBLG § Strategy for target § Proprietary libaries between partners
deconvolution
Max-Planck
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High-Throughput Screening (HTS)
The Essentials for Success
§ Chemical Compound Collection:
•  Size, Diversity, Quality, Integrity
§ Assay Reagents – Proteins, Cells:
•  Quality, Amount, Integrity, Engineered Readouts
§ Assay, Screening & IT – Technologies:
•  Physics, Lab Robotics/Automation, Data Handling
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AstraZeneca – Compound Collection
History of Collection Build
AZ project compounds
Strategic compound acquisitions
”CCE0” CCE1 CCE2 CCE3
2000 ’01 ’02 ’03 ’04 ’05 ’06 ’07 ’08 ’09 ’10 ’11 ’12 ’13
Acquisition Collection Numb of cpds
16%
Project 811 422
Projects CCE 1-3 Acquisition 280 424
46% 38%
CCE1-3 668 554
PLS total 1 760 400
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AstraZeneca – Compound Collection
Size, Composition, Novelty
Size and composition of AZ Novelty of compounds in AZ
screening collection screening collection*
21% Projects 12% 10%
11% 46% Acquisition 15% AZ publications
6% CCE1 Not public
16% CCE2 63% Acquisition
CCE3
Public domain
1.76 M compounds * according comparison with internal database which covers >50 M
compounds from the public domain (database name: ’Chemistry
Connect’)
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AstraZeneca – Compound Collection
Quality – Physicochemical Properties
Distribution for key physchem properties
s 500.000 s 500.000
nd 400.000 nd 400.000
u u
po 300.000 po 300.000
m m
Co 200.000 Co 200.000
100.000 100.000
0 0
≤-2 -1 0 1 2 3 4 5 6 ≥7
cLogP
MolWt
Comparison with third party collections
mean MW mean cLogP
DrugBank 315 DrugBank 2.4
AstraZeneca 367 AstraZeneca 2.9
GSK, Novartis, Sanofi* 386, 384, 353 BROAD 2.9
eMolecules 388 ChEMBL 3.3
ChEMBL 420 GSK, Novartis, Sanofi* 3.3, 3.1, 3.4
BROAD 511 eMolecules 3.5
*Ref: Nature Reviews Drug Discovery 10, 188-195 (March 2011)
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AstraZeneca – Compound Collection
A Key Enabler for Difficult Targets
Key elements of AZ Collection:
●  Significant size (1.76 M)
●  Significant diversity
●  Phys-chem properties (mw, clogP) screening
file
●  High quality storage (QC-criteria)
●  High capacity retrieval (acoustic)
●  Sharing with partners

Conclusions:
●  Size and composition of compound libraries (106) matter
●  Tackling of “Difficult & Unprecedented Targets” is possible
●  Quality of the compound collection is a key factor for success
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High-Throughput Screening (HTS)
Some Challenges
§ Do we need High-Throughput Screening ?
•  What are the alternatives?
§ How many HTS campaigns do we need ?
•  Attrition rate in hit discovery & drug discovery?
§ How do we run HTS campaigns ?
•  Which process, library, technology?
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Drug Discovery in Pharma & Biotech
Number of Projects per Single Product Launch
Target-to-hit Hit-to-Lead OptiLmeiazda t ion Preclinical Phase I Phase II Phase III Stou lbamuniscshi on
Launch
pp ((TTSS) ) 8800%% 7755%% 8855%% 6699%% 5544%% 3344%% 7700%% 9911%%
WIP needed for 1 launch 24.3 19.4 14.6 12.4 8.6 4.6 1.6 1.1 1
Cost per WIP per Phase $1.0 $2.5 $10 $5 $15 $40 $150 $40
Cycle Time (years) 1.0 1.5 2.0 1.0 1.5 2.5 2.5 1.5 13.5
Cost per launch (of of pocket) $24 $49 $146 $62 $128 $185 $235 $44 $873
% Total cost per NME 3% 6% 17% 7% 15% 21% 27% 5% 100%
Cost of capital 11%
Cost per launch (capitalized) $94 $166 $414 $150 $273 $319 $314 $48 $1,778
§  Low overall success - Target to Launch: RPleefa: sSe. Pseaeu la (l2s0o1: 0) Nature Rev. Drug Discovery 9, 203-214
B. Munos (2009) Nature Rev. Drug Discovery 8, 959-968
F. Pammolli (2011) Nature Rev. Drug Discovery 10, 428-438
• only 4 % PoS (= 96 % failure rate) M. Bunnage (2011) Nature Chemical Biology 7, 335-339
• 1 launch per year: 25 new targets/year
• 2 launches per year: 50 new targets/year

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Drug Discovery in Pharma & Biotech
Reasons for Failure
§   Success rate - Phase II (2008-2010):
Reasons for failure:
• Down to only 18 % (vs. 28 % in the years 2006-2007, 29% Strategic
vs. 34 % in the paper by S. Paul, NRDD, 2010)
51% Safety
• Note: 51 % termination due to lack of efficacy
19% PK/BAV
R ef: J. Arrowsmith (2011) Nature Rev. Drug Discovery 10, 328 Efficacy

1%

§  Success rate - Phase III (2007-2010): 7% Reasons for failure:
• Success rate down to only 50 % (vs. 70% in the Financial/Commercial
paper by S. Paul, NRDD, 2010) 66% 21% Safety
Not Disclosed
• Note: 66 % termination due to lack of efficacy
Efficacy
Ref: J. Arrowsmith (2011) Nature Rev. Drug Discovery 10, 87
6%

➥  Do some simple math (new probability numbers):
•  64 projects needed to generate 1 launch ??
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