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

4

HTS

Fragment

Screening

Structural

Biology

In Silico

Design

Med

Chem

DMPKIn-vitro &

In-vivo

Models

Target

Drug

Candidate

CTx 2014-15 Hit ID Process

5

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

6

• 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.

7

BRAGG Cluster 472.5 gigaflop

8

CTx VDatabase

9

• 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

10

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

11

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

12

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…….

13

Example Projects

Project 1

15

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

16

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

19

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

20

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

21

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

23

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 ?

24

My school text book map of Aus…. Queensland ….

World class Cancer biology………