Post on 27-May-2020
transcript
Integrating the Cresset Platform.
Cancer Therapeutics CRC (CTx)
G. Stevenson
June 2017
CTx: A Unique & Highly Value Adding Collaborative Model
2 Finding Cures For Cancer
CTX CRC LTD
Peter
MacCallum
Cancer
Centre
Synthesis
Research
CSIRO
Monash University
WEHI
BionomicsCTxONE Pty
Ltd
Clinical Genomics
Cancer
Trials
Australia
CCI
Sydney
NCC
Singapore
Griffith
University
www.cancercrc.com
CTx: Small Molecule Oncology Drug Discovery & Early Development Biotech Group
Finding Cures For Cancer
Partnering
Outcomes
• Refunded by CRC program 2014-20
• PRMT5i licensed to MSD 2016
• Australian CRC Association (CRCA) Award for Excellence in Innovation 2017
• Multiple projects licensed to partners
Pharma Rigour with Biotech Agility
• World renowned cancer biology with extensive
epigenetics and immuno-oncology experience.
• Application of industry focus & rigour.
– Project selection, management and review.
– Medicinal chemistry.
• Big pharma experience +++
– Commercialisation.
• High calibre industry-experienced:
– Scientific advisory board
– Board
– Management
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HTS
Fragment
Screening
Structural
Biology
In Silico
Design
Med
Chem
DMPKIn-vitro &
In-vivo
Models
Target
Drug
Candidate
CTx 2014-15 Hit ID Process
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MOE
CTx Dbase270K
XtalData
CSIRO
• HTS planned against 5 major targets ($150k/6-9 months per screen ) 270K compounds
• Processing with ~5 years remaining, success by 2018 ?
• Could enhanced in silico capability change this ?
• Options ?
Medicinal Chemistry
HTS
In Silico Options 2015
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• Outsource; Cost, particularly regarding mission creep.
• Partner in source; Low capacity, often bespoke, downstream issues.
• In house; Capacity ? License costs ? Capability ?
• Screening database; Cost and time for delivery to Australia a major factor.
• Support, backup and compatibility ?
• CTx partner access, “fit” with CRC model.
• Aim to get to faster, smarter screening.
CTx 2014-15: In Silico Strategy
• Opted for in house over CRO for efficiency and cost.
• CSIRO BRAGG cluster availability/access confirmed early 2015.
• Platform vendors identified and assessed, CRESSET chosen in mid 2015.
• CSIRO Protein production already available.
• CSIRO Xtal data already available.
• Compounds vendors approached and selected, SD files provided.
• System up and running Oct 2015.
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BRAGG Cluster 472.5 gigaflop
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CTx VDatabase
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• CTx VD, 6.9 M cmpds pre filtered. Mwt 150-550 clogP < 5.5.
• CTx collection (270K)
• ChemBl
• Vendor “active in stock” databases.
• Chembridge, SPECS, Enamine, Aurora, Maybridge, LifeCHEM, ChemDiv and BioAscent.
• Project based Vlib as required.
• Each compound is stored as up to 30 conformers.
• Order to delivery to screening running at < 1 month.
CTx Resources 2015 to date
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BLAZECSIRO BRAGGV Screening
FORGEBLAZE triage
3D QSAR
SPARKIsostere
development
TORCHSAR analysis
MOEModelling
Data WarriorCiX Tool
TorchLiteCresset Reader
MOEModelling
CTx Med Chem
CC suite
XtalData
CSIRO
CTx VDbase DotMatix
Integrated Workflow
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Forge 3D-QSAR
AlignmentSelected Molecules
BLAZE Search
Purchase ListSynthesis List
SPARK Analysis
XtalData
CSIRO
CTxVDVendor
Virtual Lib~10K
• Aim for 24-48 hour turnaround for initial results.
• Triage to purchase within one week.
• SPARK to synthesis assessed as required.
• Preparation by Med Chem group or SynMedChem.
BLAZE Triage
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Forge 3D-QSARRe-Dock
Selected MoleculesBLAZE Search
Purchase ListSynthesis List
CTx Lib Cherry pick
ChemBL Set
Vendor Set
Wet Screen
Data Mine
PhyschemActivity/Availability
IP/Cost
Aiming for;
• 1-200 compounds.
• Good developability/IP prospects.
• Low background interest.
• Delivery 2-4 weeks.
• ChemBL set mined for chemotype/target data.
Model building…………..data issues
• RAW data for 3DQSAR models is abundant……….however !
• Useable comparative data is actually quite rare.
• Assay format, target format, reporter systems, cell based, biochemical etc etc.
• Need to compare like with like, multiple variables involved.
• Check assay conditions, assess possible flaws e.g. ATP concentration in kinase assays.
• Tedious but checking original source often reveals transcription errors.
• Xtal data sets are not exempt from this, check ligand integrity etc.
• Filter on structure to develop SAR spread.
• Where possible, screen examples in house for validation.
• Even after all of this +/- 0.3 log helps…….
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Example Projects
Project 1
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Lead 200 nM
Mwt 445pKa 10.3/8.4logP 2.7LogD < 0TPSA 83
Competition x 3IP issuesDevelopability issuesReasonable xtal data
Hit 30 mMBLAZE Search
Mwt 318pKa neutrallogP 1.5LogD 1.5TPSA 73
NovelSAR ?
Lead 400 nM
Mwt 385pKa neutrallogP 3.2LogD 3.2TPSA 76
Novel
• Project at this stage was in lead ID.
• No HTS planned or carried out subsequently.
• Identified compound is novel and suitable for further development.
Single hybrid133 cmpds
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Project 2
• Lead identified for known therapeutic target, novel indication.
• Action to accelerate project in silico before HTS/MedChem start
• Could we provide novel early leads ?
Binding DB
Competitor IP
FORGE3DQSAR
Xtal data
CTx Collection Target Profile
174/07/2
017
• BLAZE search on CTx collection.
• Triage by 3DQSAR.
• 479 cmpds identified at pIC50 >6
• Colour = fit to model.
BLAZE-FORGE Virtual Screen 3D-QSAR
184/07/2
017
• BLAZE screen of 6.9 M compounds ~ 4 hours runtime on BRAGG.• Triage through 3D-QSAR model.• 1480 hits identified with prediction of activity.• Ongoing.
Project 2: Current status
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Lead 10 nM
Mwt < 500pKa 9.4logP 4.6LogD 2.4TPSA 72
Competition.IP issues.Developability issues.Reasonable xtal data.Off target activity.
Hits
BLAZE Search
Leads < 20 nMCTx Hits
TBD
Mwt < 500 < 400
pKa 9.4 neutral
clogP 3.9 3.9
clogD 1.7 -
TPSA 72 79
Novel Chemotypes
FORGE
• Analysis started 4Q 2016.• In silico hits profiled 1Q 2017 ~200 cmds.• Medicinal Chemistry started 2Q 2017.• Approx 3-4 months ahead of normal.• HTS on hold at present.
Project 3
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CTx leads< 100nM Hits
BLAZE Search
SPARK
FORGE
New chemotypeActive < 10 uM
• Challenging project.
• Flat SAR, limited chemical space to operate.
• Leads are at a premium.
• Identified chemotype offers new direction.
Current and future integrated workflow
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Forge 3D-QSAR
AlignmentSelected Molecules
BLAZE Search
Purchase ListSynthesis List
SPARK Analysis
XtalData
CSIRO
CTxVD
FLAREVlibs
ProjectLit/IP
Summary
CONFIDENTIAL22
• CRESSET platform has enabled project acceleration, it can work.
• Integration of VS-3DQSAR is highly productive.
• Further development ongoing, yes it has failed on occasion too !
• CTx consider it a major asset.
• Service available to academics both CTx and non CTx.
Acknowledgements
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Thanks to ………….
CTx: Ian Street CSO and Warwick Tong CEO for letting me do this !
CSIRO: Tom Peat and Romy Soriano.
CTx Medicinal Chemistry group, past and present.
CTx Translational biology groups, past and present.
CRESSET: M. Mackey, M. Slater, P. Tosco, G. Tedesco and D. Bardfield.
Why Australia ?
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My school text book map of Aus…. Queensland ….
World class Cancer biology………