SARomics Biostructures at a glance • Hybrid business model

- CRO generating revenues- Proprietary discovery projects

• Strategic focus on early drug discovery with a proprietary discovery platform- Unique expertise in protein structure

determination, fragment screening and in silico drug discovery

- ProPHECY™ protein optimization technology

• Experienced and skilled team- Multifaceted team of 12 persons (10 PhDs)- Entrepreneurial and scientific expertise

• Significant pharma, biotech and academic clients & partners world-wide

• Sales representatives in Boston & Japan• Five major EU R&D grants• Mission to become significant hit

generation player

GENE-TO-STRUCTURE

SARomics BiostructuresIntegrated drug discovery solutions

Gene-to-structure platform

Structure-based design solutions

Fragment-based hit generation solutions

Construct design

Cloning

Protein expression & purification

Protein characterization

Crystallization

Synchrotron-based data collection

• In silico screening• Protein production & characterization• Co–crystal lead structure determination

• Biophysics-based screening• Hit identification & SAR exploration• Co–crystal fragment structure

determination

Off-the-shelf protein structures• FastLane™ library• Focus on kinases and epigenetic

targets

State-of-the-art crystallization labSARomics Biostructures performs high-throughput low volume

crystallization using liquid handling, crystallization and imaging robotics

Microlitre robot

Crystallization roboticsPlate hotel/imaging robotics

Synchrotron accessWe currently ship crystals to Diamond Light Source (DLS), Oxford,

and BESSY, Berlin, on average twice/monthWe are located in close vicinity to the Swedish synchrotron MAX IV

and when it opens we will have rapid access to beamlines

A wide range of technologies are used to characterize ligand binding and protein behavior using biophysical principles

Biophysics-based screeningand protein characterization

Ligand binding• NMR screening (96 tube sample changer)• NMR analysis/titration• DSF (thermofluor-based method, 96 wells)• ITC• MST

DLSDSF NMRCDITC

Protein characterization• DSF (thermofluor-based method, 96 wells)• DLS (96 well format)• Buffer screen (DLS+DSF)• CD• NMR

Access to structural information increases your understanding and enables you to execute projects faster

Extensive experience in Fab–antigen crystallization & structure determination

Use structural information for:1. Epitope definition to file stronger IP2. Understanding MoA3. Structure-based design4. Antibody engineering: affinity maturation5. Antibody engineering: humanization6. Antibody engineering: ADC7. Structural characterization of protein drugs

FASTLANE™ LIBRARY

FastLane™ structures

Standard

*Please see www.saromics.com for a complete list.

Proteins* ready to be expressed, purified and crystallized according to existing verified protocols (complexes delivered within 4 to 10 weeks)

• >55 kinases

• >30 phosphatases

• >20 bromodomains

• >20 demethylases

• >30 other targets

Crystallization system up and running and ready to be co-crystallized with customers compounds (complexes delivered within 2 to 6 weeks)

Kinases:BTK, CK2, DAPK3, PFKFB3, PIP4K2A, PLK4, STK17BEpigenetics targets:KDM4C, ATAD2A & 2B (bromodomains)Proteases:USP8, Cathepsin C, ThrombinOther:AR, BCAT2, BlaC, DHODH, Gal3C, Hsp90, IL-17A, LDHA, PDE4d, PTP1B, S100A4, S100A9, S100A12, TIM3, TNFα

Premium

Soon also: Hif2α, KDM4a-d, KDM6a, LSD1, RORg

FastLane™ structuresCase study I

From FastLane™ Standard to 3D structure in 2.5 weeks• Expression and crystallization of ATAD2A bromodomain

• Followed verified protocols

• Final structure resolution 1.65 Å (compared to published 1.95 Å)

ATAD2AATAD2A with bound thymine

FastLane™ structuresCase study II

From FastLane™ Standard to 3D structure in 10 days• Purification and crystallization of KDM4C histone demethylase

• Followed verified protocols

• Final structure resolution 2.50 Å (compared to published 2.55 Å)

KDM4C (or JMJD2C) KDM4C (or JMJD2C) in complex with (2,4-PDCA)

FastLane™ structuresCase study III

Delivery of refined structure 3 days after receiving compound• PFKFB3 established as FastLane™ structure

• Tuesday: Received compound by FedEx

• Wednesday: Soaking of compound into available crystals

• Thursday: Data collection to 2.8 Å (911-3 beamline)

• Friday: Structure refinement and delivery of results to customer

PFKFB3 – 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase

FastLane™ structuresCase study IV

Proprietary crystallization system for IL-17A• Generated several small molecule ligand complexes

• Enables both co-crystallization and soaking into apo crystals

• Resolutions ranging from 2.2 – 3 Å

• No Fab fragment present

FRAGMENT-BASEDSCREEINING

STRUCTURE-BASEDDRUG DESIGN

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FRAGMENT LIBRARY SCREENING, VALIDATION & FRAGMENT EXPANSION/ELABORATIONCollaboration between SARomics Biostructures & Red Glead Discovery

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FragmentscreeningScreeningtechnologies

InsilicoscreeningThermoshiftassay(DSF)

NMRWAC

Biochemicalscreening(HCS)X-raycrystallography

MST

CompoundsProprietarylibrary

SpecificallyorderedsetsClientlibraries

• Medicinalchemistry

• Synthesis:smallmolecules&peptides

• Analyticalchemistry(NMR&MS)

• Invitrobiology• InvitroADME&physchem

• HTS/FBLGexpertise

• Structure-baseddrugdesign• X-raycrystallography• Computationalchemistry

• NMRscreening

• Biophysics• Proteinchemistry

A collaborative innovative screening platform

Crystallographic fragment screening

• High-throughput low volume crystallization capability

• Soaking pools of fragments

• Co-crystallization of selected fragments

• High-throughput data collection (at automated synchrotron beamlines)

• Structure determination and refinement through automated data pipelines

Crystallization robotics

MAX IVDLS

In silico screening using Schrödinger computational technology

Glide - Complete solution for ligand-receptor docking

Phase - High-performance program for ligand-based drug designStrike - Powerful software for statistical modeling and QSARPrime - Powerful and innovative package for accurate protein structure predictionsSiteMap - Fast, accurate, and practical binding site identificationLigPrep - Versatile generation of accurate 3D molecular modelsMacroModel - Versatile, full-featured program for molecular modeling

Liaison - Efficient and accurate ligand-receptor binding free energy prediction

QikProp - Rapid ADME predictions

Canvas - CheminformaticsJaguar - Rapid ab initio electronic structure calculationEpik - Rapid and robust pKa predictions

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Weak binding fragments require binding to be detected by biophysical principles

Typical fragment screening technologies:• CFS - crystallographic fragment screening• DSF - differential scanning fluorimetry (or thermal shift, TSA)• WAC - weak affinity chromatography• NMR - ligand detected• NMR - protein detected• [SPR - surface plasmon resonance (BIAcore)]• MST - microscale thermophoresis• HCS - high concentration biochemical screening

DSF NMR CFS

Biophysics-based screening

Ultra high field NMR instrumentsAccess to NMR instruments at the Swedish NMR Centre

Automatic assignment, NUS sampling, fragment screening etc.

• 900 MHz Bruker Avance III HD– 4 RF channels– Triple-axis pulsed field gradients– TCI cryoprobe (1H/13C/15N, 5 mm)– Triple resonance probe (1H/13C/15N)

• 800 MHz Bruker Avance III HD– 4 RF channels– Triple-axis pulsed field gradients– TCI cryoprobe (1H/13C/15N, 3 mm)– SampleJet

• 800 MHz Bruker Avance III HD– 4 RF channels– Triple-axis pulsed field gradients– TXO cryoprobe (1H/13C/15N, 5 mm)– Triple resonance probe, 8 mm

• 3x600 MHz Varian Inova/Bruker– 3-4 RF channels– Triple-axis pulsed field gradients– Tripple resonance cryo-probe (1H/13C/15N)– Triple resonance probe (1H/13C/X)– 4 mm NANO probe– Diffusion probe (1H/2H/19F)

Ligand detected NMR screening

• Sample changer screens 96 samples overnight

• Cryo probe equipped 800 MHz NMR instrument

• Ligand observed NMR spectra

• NMR analysis/titration of selected hits

• Typically pools of 4-6 cmpds

• Capacity: ~500 cmpds per day

• Performed at the Swedish NMR Centre

NMR screening – verification

(S1):compound in buffer

(S2):compound in buffer +target

(S3):compoundinbuffer+target+refcmpd

• Automatic compound QC• 500 MHz in-house and 600 MHz at nearby Lund University• Solid NMR expertise

Differential Scanning Fluorimetry (DSF)Initial screening (1ary or 2ndary assay)

Dose response curves

Biochemical assay and/or NMR

X-ray – soaking/co-crystallization(very predictive for X-ray success)

0.1 mg /ml 0.2 mg/mlΔTm at 62.5 µM ΔTm at 62.5 µM

RG200001 5.95 7.3RG200001 6.3 6.4RG200002 9.6 10.4RG200002 10.2 10.7RG200003 -1.3 -0.48RG200003 -0.9 -0.76

MicroScale Thermophoresis (MST)

• Quantification of molecular interactions• Measures the motion of molecules along microscopic

temperature gradients• Access affinities (Kd, dissociation constant): nM to mM range• Rapid assay optimization• Fast measurement: Kd in 10 min• Low sample consumption: minimal concentration (nM) and

small volume (< 4 µl)

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• WAC™attractiveasprimaryfragmentscreeningassay

• InventedbyProf.Sten Ohlson (LinnaeusUniversity,Kalmar,Sweden)

• CommercialrightsbyTransienticInteractionsAB(TI)

• SARomicsandRGDinuniquecollaborationwithTItosetupexclusiveserviceplatform

Screening using Weak Affinity Ahromatography (WAC™)

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• TargetproteinimmobilizedonHPLCcolumn• Retentiontimeoffragmentsrelatedtoselectiveinteractionswithtarget• Physiologicalbufferusedasmobilephase• Kd candirectlybecalculatedfromretentiontime• Highthroughputpotential(upto3000-4000fragmentsperday?)

Fragment screening by WAC™

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WAChassignificantadvantagescomparedtotheothermethodsintermsofspeedandinformationprovided.

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• GoodcorrelationwithNMR,SPRandX-ray

• MoresensitivethanSPR• IndicativeforX-ray

Screeningof111fragmentsbyWAC,NMR,SPR,FPandTmshift.Selected

fragmentsalsobyITCandX-raycrystallography.Fragmentslisted

withdecreasingaffinitiesasmeasuredbyWAC.

(Meiby etal.2013,Anal.Chem.,85,6756)

WAC™ versus other techniques

Casestudy:Screening155fragmentsonaBRD4-column

• UsingaWAC-cutoffofΔtret >5min,allfragmentsverifiedbyothertechniquesexcept:• RG200054andRG200067(”Pfizer-hit”)• RG210010nottestedinotherassays.

A=active;NA=notactive;NT=nottested

CompoundID Δtret (min)WAC Biochem DSF NMR X-rayRG210073 138.1 A(dose-response) A NT YESRG210080 87.2 A(dose-response) A NT YESRG210074 71.4 A(dose-response) A NT YESRG210069 52.1 Tendencyofactivity A NT YESRG210070 42.1 Tendencyofactivity A NT YESRG210081 35.1 A A NT YESRG210079 28.3 A A NT YESRG210019 10.7 NA A NA NT

RG200067 9 NA NA NA NT

RG100104 7.6 NT NA A NT

RG200054 7.3 NA NA NT NT

RG100056 6.8 NT NT A NT

RG210010 5.9 Nottestedinanyotherassay

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Fragment library

WAC

DSF + QC NMR/MST (if needed)

Fragment in crystal structure

Expansion of fragments

Screening

Validation of Actives

Furthervalidation

Crystallization & structure determination

Analysis of fragment binding

Hit IDEffect in

bioassay?Hit

quality?

Recent collaborative publicationsAstraZeneca/Royal Institute of Technology

“Crystal structures of the Chromobacteriumviolaceum ω-transaminase reveal major structural rearrangements upon binding of coenzyme PLP.” Humble et al., 2012, FEBS J, 279, 779-79.

Lund University/ESS

“Structural basis for carbohydrate-binding specificity -a comparative assessment of two engineered carbohydrate-binding modules.” von Schantz et al., 2012, Glycobiology, 22, 948-61.

“Carbohydrate binding module recognition of xyloglucan defined by polar contacts with branching xyloses and CH-π interactions.” von Schantz et al., 2014, Proteins, 82, 3466-75.

“Neutron Crystallographic Studies Reveal Hydrogen Bond and Water-Mediated Interactions between a Carbohydrate-Binding Module and Its Bound Carbohydrate Ligand.” Fisher et al., 2015, Biochemistry, 54, 6435-8.

Arsanis Biosciences

“Structure-Function Analysis of Heterodimer Formation, Oligomerization, and Receptor Binding of the Staphylococcus aureus Bi-component Toxin LukGH.” Badarau et al., 2015, J Biol. Chem., 290, 142-56.

“Context matters: The importance of dimerization-induced conformation of the LukGH leukocidin of Staphylococcus aureus for the generation of neutralizingantibodies.” Badarau et al., 2016, Mabs. 8, 1347-1360.

Galecto Biotech/Lund University

“The carbohydrate-binding site in galectin-3 is preorganized to recognize a sugarlike framework of oxygens: ultra-high-resolution structures and water dynamics.”Saraboji et al., 2012, Biochemistry, 51, 296-306.

“Protein flexibility and conformational entropy in ligand design targeting the carbohydrate recognition domain of galectin-3.” Diehl et al., 2010, JACS, 132, 14577-89.

Cancer Research Technology, UK

“Fragment library design considerations.”Boyd et al., 2012, WIREs Comput. Mol. Sci., 2, 868-885.

“Fragment-based drug discovery and protein-protein interactions.”Turnbull et al., 2014, Research and Reports in Biochemistry, 4, 13-26.

ETH

“De Novo Fragment Design for Drug Discovery and Chemical Biology.”

Rodrigues et al., 2015, Angew Chem Int Ed Engl., 54, 15079.

Sahlgrenska Cancer Center

“Cancer differentiation agent hexamethylene bisacetamide inhibits BET Bromodomain proteins.”

Nilsson et al., 2016, Cancer Res., 76, 2376-83.

MD

Fragment screening

Fragment expansion

Hit seriesexpansion

Lead series identification

Lead optimization Partner

Internal discovery pipelineC

ance

r

merozyne

SBX-1401 TAKTIC NIK kinase inhibitor

SBX-1301 BRD4 epigenetic inhibitor

SBX-1501 Pim-1 kinase inhibitor

KINOMED Kinase inhib.

Merozyne Therapeutics

SBX-1402 mAb

HeadquartersMedicon Village • SE-223 81 Lund • Sweden

Tel: +46 46 26 10 470

US branch245 First Street • Cambridge • MA 02142

Tel: 508 269 9048

Björn WalseCEO

SARomics Biostructures ABbjorn.walse@saromics.com

Tel: +46 46 26 10 470

www.saromics.com

Japanese distributorCarna Biosciences. Inc.

1-5-5 Minatojima-MinamimachiChuo-ku • Kobe • Japan

Tel: +81 78 302 7091