Structural insight increases your understanding and enables you to execute projects faster

SARomics Biostructures at a glance •  Strategic focus on early drug discovery •  Proprietary discovery platform

-  Unique expertise in protein structure determination and in silico drug discovery

-  ProPHECY™ protein optimization technology

•  Hybrid business model -  Proprietary discovery projects -  CRO generating revenues

•  Experienced and skilled team -  Entrepreneurial and scientific expertise

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

•  Three major EU R&D grants •  Mission to become significant hit

generation player

SARomics Biostructures Integrated 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

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

•  >40 phosphatases

•  >30 bromodomains

•  >20 demethylases

•  >20 other targets

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

Kinases: CK2, Pim-1, Vps34, PFKFB3 Epigenetics targets: KDM4C, ATAD2A & 2B (bromodomains) Proteases: USP8, Cathepsin C (licence for SBDD included) Other: Hsp90, PDE4d, DHODH, Aldose reductase M. tuberculosis beta-lactamase (BlaC)

Premium

Soon also: Pim-2, DAPK3, DDR1, KDM4a-d, KDM6a

FastLane™ structures Kinases

Other targets

Please see complete list at: www.saromics.com

FastLane™ structures Case study I

From FastLane™ Standard to 3D structure in 2.5 weeks

•  Expression and crystallization of ATAD2A bromodomain

•  Followed verified protocols from The SGC

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

ATAD2A ATAD2A with bound thymine

FastLane™ structures Case study II

From FastLane™ Standard to 3D structure in 10 days

•  Purification and crystallization of KDM4C histone demethylase

•  Followed verified protocols from The SGC

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

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

Don’t work in the dark!

Access to 3D structural information increases your understanding and enables you to execute projects faster

Fab–antigen structures

Use structural information for: 1.  Epitope definition enabling stronger IP 2.  Understanding mode of action 3.  Structure-based design 4.  Antibody engineering: affinity maturation 5.  Antibody engineering: humanization 6.  Antibody engineering: ADC 7.  Structural characterization of protein drugs

Synchrotron access Our lab is located “down the hall” from the crystallography beamlines at the MAX IV Laboratory, which provides us with

extremely rapid access to synchrotron beamtime

Our future light source

•  SARomics will be in a very advantageous position for access to MAX IV in 2016 •  Access to the world’s most advanced synchrotron source will substantially

increase our competitiveness •  SARomics will be a key player in leveraging industrial usage of MAX IV

September, 2014

State-of-the-art crystallization Lab

SARomics Biostructures performs high-throughput low volume crystallization using liquid handling, crystallization and imaging robotics

Microlitre robot

Crystallization robotics Plate hotel/Imaging robotics

Ultra high field NMR instruments

Access to NMR instruments at the Swedish NMR Centre Automatic assignment, NUS sampling, fragment screening etc.

•  900 MHz Bruker Avance III –  4 RF channels –  Triple-axis pulsed field gradients –  Triple resonance cryo-probe (1H/13C/15N) –  Triple resonance probe (1H/13C/15N)

•  800 MHz Bruker Avance III –  4 RF channels –  Triple-axis pulsed field gradients –  Triple resonance probe (1H/13C/15N) –  SampleJet

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

•  2x600 MHz Varian Inova –  4 RF channels –  Triple-axis pulsed field gradients –  Double resonance cryo-probe (1H/13C) –  Triple resonance probe (1H/13C/X)

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

Biophysics-based screening/characterization

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

DLS DSF NMR CD ITC

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

Schrödinger Computational Technology

Glide - Complete solution for ligand-receptor docking

Phase - High-performance program for ligand-based drug design Strike - Powerful software for statistical modeling and QSAR Prime - Powerful and innovative package for accurate protein structure predictions SiteMap - Fast, accurate, and practical binding site identification LigPrep - Versatile generation of accurate 3D molecular models MacroModel - Versatile, full-featured program for molecular modeling

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

QikProp - Rapid ADME predictions

Canvas - Cheminformatics Jaguar - Rapid ab initio electronic structure calculation Epik - Rapid and robust pKa predictions

SARomics currently holds a license to the following modules:

Collaborators

inSili.com, Zürich, Switzerland - Proprietary de novo molecular design technology

Red Glead Discovery, Lund, Sweden - Medicinal chemistry, assay development and screening

Xbrane Bioscience, Stockholm, Sweden - Proprietary protein expression technology

Nobody can work alone these days. We have formed alliances with the following companies:

SARomics Biostructures – inSili.com discovery alliance

•  Consulting and contract research organization •  Founded 2013 as a ETH (Zürich) spin-off •  Provides know-how and world-leading technology for virtual

screening of pioneering de novo designed molecular agents

Objective for collaboration:

•  Will identify drug-like ligands for SARomics x-ray targets by unique and proprietary virtual screening and de novo design technologies

•  Merging unique and highly complementary capabilities of the two companies •  Proprietary lead discovery projects •  Customer sponsored projects

Leads by design

Angew. Chem. Int. Ed. 2013, 52, 10006-10009.

•  Reaction-based molecular de novo design •  Generating new chemical entities (NCEs) from known molecules

Design of selective Plk-1 inhibitors

A collaborative innovative screening platform

Currently performing proprietary project “PILOT” aiming to discover and optimize novel compounds inhibiting an hot epigenetic target for oncology

indications using fragment-based hit generation

Fragment screening Screening technologies

Virtual screening methods High-concentration

screening X-ray crystallography &

NMR

Compounds Proprietary library

Libraries from customer

• Medicinal Chemistry & NMR

• Peptide Chemistry

• In vitro biology

• In vitro ADME & PhysChem

• HTS/FBLG expertise

• Translational science expert

• Structure-based drug design

• X-ray crystallography

• Computational chemistry

• NMR screening

• Biophysics

• Protein chemistry

Project Indication Target Type (frag/hit/lead) Partner

PILOT Cancer Epigenetic frag/hits

KINOMED* Cancer CK2/Pim-1 frag (dual)

TAKTIC# Cancer 3 kinases hits

SARTRIC* Antibacterial Regulator hits

Internal discovery pipeline

#FP7 funded project *Eurostars funded project

Pim-1 CK2

Crystal structures of Pim-1 and CK2 in complex with a dual binding fragment

Pim-1/CK2 dual binding fragments

1040 fragments were screened against CK2 and Pim-1 at a concentration of 100 µM Hit rate of 3% (Pim-1), 2% (CK2)

Most fragments are selective for either CK2 or Pim-1 1 % of fragments inhibit both enzymes

FP7 financed project with goal to discover and optimize novel compounds inhibiting three protein kinases that are involved in the regulation of the

transcription factor NF-kB, a key regulator of tumor cell growth FP7 (EU) funding: 1.15 M€

2 year project: February 2013 - January 2015

TAKTIC: TrAnslational Kinase Tumour Inhibitor discovery Consortium

Funded by FP7 under the program: “Research for the benefits of SMEs”

BioVersys and SARomics Biostructures join efforts to combat multidrug-resistant

bacterial infections

•  Antimicrobial resistance represents a major threat to public health worldwide •  The SARTRIC project addresses this deficiency by restoring vancomycin

activity by blocking the transcriptional activation of resistance genes •  Two highly complementary technology modules will be combined to drive the

drug development process •  Part of the project will be financed by a 260 kEuro Eurostars grant (total

budget 1.6 mEuro)

Our latest publication

Turnbull, Boyd & Walse (2014) RRBC, 4, 13-26.

Reviewed recently by the Practical Fragment blog

Recent collaborative publications

AstraZeneca/Royal Institute of Technology “Crystal structures of the Chromobacterium violaceum ω-transaminase reveal major structural rearrangements upon binding of coenzyme PLP.” Humble et al., 2012, FEBS J, 279, 779-79.

Lund University “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.

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.

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.