Increasing compound collection value and diversity … diversity through collaborations, partnerships, and open-innovation ... AZ Collabn National Cmpd Collection ... SSD) Still challenging

Increasing compound collection value and diversity through collaborations, partnerships, and open-innovation

Thierry Kogej

AstraZeneca R&D - Discovery Sciences – Chemistry Innovation Centre

ChemAxon – User Group Meeting – 18-20th May 2015

Current Challenges in early drug discovery

2 IMED Biotech Unit I Discovery Sciences

Declining success rates

Same old target space

Reduced investment in R&D

Increase collaboration/partnership

http://www.google.se/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.forbes.com/sites/matthewherper/2011/06/27/the-decline-of-pharmaceutical-researchmeasured-in-new-drugs-and-dollars/&ei=MfM5VeOvJsfBPPaogMAI&bvm=bv.91427555,d.d2s&psig=AFQjCNFLOBIdQlTu-NW446ozL1t1JacNKw&ust=1429947564522012

http://www.google.se/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.forbes.com/sites/matthewherper/2011/06/27/the-decline-of-pharmaceutical-researchmeasured-in-new-drugs-and-dollars/&ei=MfM5VeOvJsfBPPaogMAI&bvm=bv.91427555,d.d2s&psig=AFQjCNFLOBIdQlTu-NW446ozL1t1JacNKw&ust=1429947564522012

Remit of AZ Early Discovery Partnering


External Discovery Platform


Many single disease

area collaborations

Support Neglected

Diseases

TBDA

IMI Lead Factory consortium

(European academia and EFPIA) Strategic Partnering

with Academic LG

Centres of Excellence

Multi-Target

opportunities

Increase

value of

screening

collections

AZ Collabn

National Cmpd

Collection

Innovative

chemistry:

Increase

diversity &

quality of

leads

AZ Compound

Collection

Multi-Target

First refusal

http://www.alchemia.com.au/Home.aspx


Outlines of the talk


Part 1. Cross HTS screening

AZ-Bayer screening collaboration

Part 2. Profiling novel compounds from Academia/CRO’s

Open Innovation portal

Part 3. Profiling external chemical libraries

Increase diversity & quality of lead molecules

https://www.google.se/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=https://www.chemaxon.com/&ei=lfg5VY8egbk9_7yBmA4&bvm=bv.91427555,d.d2s&psig=AFQjCNFisJOfnzNLzFcxWInOdNigOuBM_Q&ust=1429948936585314

https://www.google.se/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=https://www.chemaxon.com/&ei=lfg5VY8egbk9_7yBmA4&bvm=bv.91427555,d.d2s&psig=AFQjCNFisJOfnzNLzFcxWInOdNigOuBM_Q&ust=1429948936585314


Part 1: Cross HTS screening

Bayer Pharma HC - AstraZeneca ‘Boomerang’ project – a successful example of peer-peer collaboration


• Pioneering Joint initiative established between AstraZeneca and Bayer in 2010 (extended to 2016)

• Enables both parties to seek chemistry starting points not available in their internal collections

Active / HitParties provides assay development to prosecute

HTS and lead cascade

Lead

Optimisation

Bayer Pharma HC AstraZeneca

Nominate HTS Target Nominate HTS Target

Screen

Target swap

Transfer chemical series

Progression through milestone and royalty payments

Overlap of Bayer Pharma HC and AstraZeneca collection – Identical fingerprints


Big pharma screening collections: more of the same or unique libraries? The AstraZeneca-Bayer Pharma AG case

Kogej T, Blomberg N, Greasley PJ, Mundt S, Vainio MJ, Schamberger J, Schmidt G, Huser J. Drug discovery today (2013).

*) As we are not sharing structures for analysis the overlap is based on exact

match of molecular fingerprints (ECFP4). This is an overestimate of identity

as a small fraction of non-identical compounds will have the same fingerprint

*

3.3% of the total collection (Bayer + AZ is overlapping)

95% of the overlap are public domain compounds

Screening of > 4.2 Millions unique cmpds


Part 2: Profiling novel compounds from Academia/CRO’s

AstraZeneca Open Innovation Website


http://openinnovation.astrazeneca.com/

http://openinnovation.astrazeneca.com/

New Molecule Profiling


Description

Partner can submit novel compounds to be part of the AZ HTS collection

Quick assessment of the novelty and physchem profiles

Transfer of samples supported by AZ

AZ reports sample activities and discuss further options

Partner retain full intellectual property (IP) on their compounds

Requirements

No structure disclosure to AZ

no IP contamination

Check novelty and physchem profile need structure standardization

New Molecule Profiling – Current process


Academia/CRO’s

ChemAxon

ChemInformatic

assessment

AZ and Pubchem

(2D fingerprint format)

Update every quarter

AstraZeneca

Outsource the cheminformatic assessment to a third party

ChemAxon was selected as the preferred partner

Scope of work

Establish legal agreement with the submitters

Manage structures transfer to ChemAxon (formatting)

Structures standardization/molecular fingerprints generation

Novelty check against AZ and PubChem

Identify controlled substances

Physchem properties calculation

Generate report and submit to AZ for review

https://www.google.se/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=https://www.resourcenter.net/Scripts/4Disapi07.dll/4DCGI/events/2010/245-Exhibitors.html?Action=Conference_Detail&ConfID_W=245&ConfID_W=245&ei=VK80VZXNMajMyAOrzoFg&bvm=bv.91071109,d.bGQ&psig=AFQjCNHHL0UshfgRE8eg-gNC6bPB2RkbJQ&ust=1429602475387406


http://www.google.se/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.muhammadsakil.com/2015/04/adobe-reader-free-download.html&ei=IAs2VYPRF8r4ywPI-oDwDg&bvm=bv.91071109,d.bGQ&psig=AFQjCNFzjjNU4MsTT8uosT_F9GidNaKlPQ&ust=1429691544323342

http://www.google.se/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.muhammadsakil.com/2015/04/adobe-reader-free-download.html&ei=IAs2VYPRF8r4ywPI-oDwDg&bvm=bv.91071109,d.bGQ&psig=AFQjCNFzjjNU4MsTT8uosT_F9GidNaKlPQ&ust=1429691544323342



Cheminformatic report


MW cLogP

RotB Aliph

Ring

Arom

Ring

Nitrogen

Fsp3

Oxygen

New Molecule Profiling – Future development


Give access to

partners to a larger set

of predictions for their

cmpds

QSAR AZ models

Developed in

collaboration between

Genetta Soft AB,

Uppsala University, and

AstraZeneca R&D

www.bioclipse.net

http://www.bioclipse.net/


Part 3: Profiling external chemical libraries

Cheminformatics assessment of external collections

16IMED Biotech Unit I Discovery Sciences

Making every SAR point count: the development of Chemistry Connect for the large-scale

integration of structure and bioactivity data.

Muresan S, Petrov P, Southan C, Kjellberg MJ, Kogej T, Tyrchan C, Várkonyi P, Xie PH. Drug

Discov Today. 2011, 16, 1019-30

Novelty to AstraZeneca



Prop. Filters Chem. Filters

Core No violation No match

Back-Up 1 violation No match

Ugly no matter >= 1 match

Ugly >= 2 violations no matter

Chemical filters

~150 chemistry alerts (11 classes (e.g. reactives, unwanted structures,…)

Property filters

100 MW 550

-2 ClogP 6

1 PSA 160

AZFilters

Alerts:

Genotoxicity via Bursi alert

Reactive Metabolite

PAINS structures

Chemical predictive modelling to improve compound quality

Cumming JG, Davis AM, Muresan S, Haeberlein M, Chen H. Nature

Review Drug Discovery, 2013, 12, 948-62


Compound

filters and alerts

AZ collection

>20 % have 2 aromatic and 1 aliphatic rings




Compound

filters and alerts

Physchem

Ex. Combined ring information

“many”



0

20

40

60

80

100A’

B’

C’

% o

f cpds

AZ collection Alchemia ’sub-library’

Alchemia

compounds

populate more

3D space

O

NH

OOH

O

OO

NH2


Compound

filters and alerts

Physchem

Molecular Complexity

Bioactive Molecules: Perfectly Shaped for Their Target?

Wirth M, Sauer WHB. Molecular Informatics. 2011, 30, 677–88

A’B’

C’

Fsp3, Chirality,

PMI...

Principal Moment of Inertia





DNP

148k

CCEPR

325k

Organic

HEV > 15

MW < 450

-2 < AlogP < 5

60k

311k

Random

selection

50k

50k

45+45k Bayesian classifier

FCFP_6

Number of rings

Number of aromatic rings

5k

5k

Test

model

[Have tried different variants]

AUC for ROC (TPR v. FPR): 0.999

Best split: -22.85

Score > -25 is associated with ”natural product like” cmpd


Compound

filters and alerts

Physchem


Natural Product-likeness Score and Its Application for Prioritization

of Compound Libraries

Peter Ertl,* Silvio Roggo, and Ansgar Schuffenhauer

J. Chem. Inf. Model. 2008, 48, 68-74

Natural Product

likeness zone



Filter collection to include cmpds with 25 <

HAC < 40

Generate 3D struct. (max 100 conf/cmpd)

Run ROCS (different Tanimoto thresholds

depending the query)

3D Know mimetics:

a-helix i.e. nutlins

b-strand i.e. peptidomimetics

PPI co-crystallized X-ray structures

ACS Med. Chem. Lett. 2013, 4, 660

JACS 2011,133,14220


Compound

filters and alerts

Physchem


3D shape/2D search

2D structures:

Macrocycles, spiro scaffold, “ring of the

futures”, privileged structures

OpenEye tools

tools




Compound

filters and alerts

Physchem


3D shape/2D search

2D Fingerprint-based

Similarity/diversity

Clustering

Assessment based on 2D fingerprint (Tanimoto – ECFP4)

Similarity to active cmpds from ChEMBl, GVKBio, etc…to enrich

AZ biological active space

Diversity to AZ collection

2D fingerprint and “Murcko” scaffolds

Ensure good coverage of the external collection

Reduce singleton exposure

Visual inspection

… last but not least, review from

medicinal chemists

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.unclewalter.info/2013/04/my-top-20-cartoon-characters.html&ei=Qcc4VbVeyaywAZ-SgMAP&bvm=bv.91427555,d.bGg&psig=AFQjCNGkL_E4IibGnP9tKJIc7wQMMerwgQ&ust=1429870747765918

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.unclewalter.info/2013/04/my-top-20-cartoon-characters.html&ei=Qcc4VbVeyaywAZ-SgMAP&bvm=bv.91427555,d.bGg&psig=AFQjCNGkL_E4IibGnP9tKJIc7wQMMerwgQ&ust=1429870747765918

Cheminformatics IT platform


Linux cluster

2D Fingerprint-based Similarity/diversity



No IP issue

a priori no limitation on CPU time

Limited choice on the software platform (license issue)

Range of properties limited by the platform choice

Sharing protocols

(Pipeline Pilot)

Linux cluster



No IP issue

a priori no limitation on CPU time

Limited choice on the software platform (license issue)

Range of properties limited by the platform choice

Use for projects with high IP restriction

(no network, disk format)

Current laptops are sufficiently powerful to

generate a rich collection analysis with limited time

Sharing protocols

(Pipeline Pilot)

Linux cluster

Isolated laptop

Novelty to AstraZeneca Compound filters and alerts


3D shape/2D search

2D Fingerprint-based Similarity/diversity

Clustering

Physchem

~1 hour / 1 million cmpds

Murcko

Structure standardization

~12 hours, ECFP4, 2 million x 2 million cmpds

(ICore7, 8 threads, SSD)

Still challenging

but done on properly

limited sets

Conclusion


Cross HTS partnership as a way to increase size of screening collections

AZ Open Innovation portal to gather and profile novel compounds from Academia/CRO’s

Profiling external chemical libraries

large set of relevant properties to access external collection value

Adapted platforms to fit different collaboration requirements

Increase diversity & quality of lead molecules

Acknowledgement


AZ/Bayer Alliance

Kirsty Rich, Peter Greasley, Niklas Blomberg, Peter Simpson, Isabella Feierberg

Bayer: Bernd Kalthof, Jens Schemberger, Georg Schmitt, Stefan Mundt, Jöerg Hϋser, Hanno Wild

New Molecule Profling

Phil Spencer, Dave Cosgrove, Ernst Ahlberg Helgee, Isabel Charles, Matthew McLoughlin, Clive Green

ChemAxon

Cheminformatics platform

Ola Engkvist, Michael Kossenjans, Ulf Börjesson, Wolfgang Klute, Loredana Spadola, Toan Mguyen, Jens Sadowski

Thanks for your attention

Question?

IMED Biotech Unit I Discovery Sciences28

Backup


Current statistics of submission


Low attribution between cmpds submission and incorporating them into HTS plates

Cheminformatics recommendation mainly driven by novelty to AZ collection

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F: +44 (0)20 7604 8151, www.astrazeneca.com

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Increasing compound collection value and diversity … diversity through collaborations, partnerships, and open-innovation ... AZ Collabn National Cmpd Collection ... SSD) Still challenging