INTEGRATED

DRUG DISCOVERY

CAPABILITIES

Selvita Services

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• Target validation

• Hit identification

• Hit to lead

• Lead optimization

• Preclinical candidate nomination

• Broad target class and disease area expertise

• Quality Control

• Release Analyses

• Impurity Studies

• Method Development and Validation

• Synthesis process optimization

and parametrization

• Scale-up of processes

& technology transfers

• Custom synthesis of NCEs, impurities/

metabolites identification and synthesis

• Isotope labelling (2H, 13C, 15N)

• Computational chemistry

Drug discovery services Regulatory Research and development

Comparative studies of biosimilar

products

• Pharmacodynamic studies

• Crystallography

• Proliferation studies in vitro

• Metabolic studies in vitro

• Process related impurities measurement

Support for drug discovery in the areas of:

• Medicinal/Synthetic chemistry

• Assay development & screening

• In vitro pharmacology

• ADME/DMPK

• Protein production & crystallography

• CADD/ AI-driven drug discovery

Leading partner for Integrated Drug Discovery

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• Target validation

with a genetic and

pharmacological

approach

• Biomarker expression

and post-translational

modifications

• Cellular processes

• Assay development

and screening

• HTS

• vHTS

• Fragment-based

drug design

• Structure- and ligand-

based drug design

• Biophysical methods

• Medicinal and synthetic chemistry

• Computer Aided Drug Design

• Primary and secondary assays

• Protein production

• Protein crystallography

• ADME/DMPK

• In vitro pharmacology

• In vivo pharmacology

• Selection of

a preclinical candidate

to initiate IND-enabling

studies

PRECLINICAL CANDIDATE

LEAD OPTIMIZATIONHIT TO LEADHIT IDENTIFICATIONTARGET VALIDATION

ARTIFICIAL INTELLIGENCE (AI)-ASSISTED DRUG DISCOVERY

EXTENSIVE DRUG DISCOVERY EXPERTISE IN VARIOUS THERAPEUTIC AREAS

• AI-assisted structure design

• Prediction of ADME properties

• AI-assisted vHTS• Prediction of

interactions/binding

sites MOA (AI tools)

CLIENT CORE EXPERTISE

SELVITA BIOLOGY SELVITA ADME/PK

SELVITA CADD & MEDCHEM

Building a best fit for the project

We offer individual stand-alone capabilities

or multidisciplinary packages across

chemistry and biology

to support diverse client needs.

Selvita offers flexible support exactly

where & when our customer projects

require it.

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We build an optimal fit between our client’s core expertise, Selvita capabilities and project’sstrategic goals

Flexible approach to multidisciplinary projects

Tight organization of scientific activities speeds the drug discovery process

Flexible fit for a partner’s changing needs

Good match between partner’s and Selvita’s core competences and strengths

Benefits for our partners:

Medicinal Chemistry support Hit confirmation Hit to Lead/

Lead Optimisation

Chemistry

ADME

CompChem

Chemistry

Biology ADME

CompChem

X-raycrystallography

ADME/DMPK

BiologyMedChem

In vivo models

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Robust drug design feedback loop

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CLOSELY

COOPERATING

EXPERTS

SYNTHESIS

ANALYSIS

BIOLOGICALEVALUATION

DATA SHARING

DATA

EVALUATION

COMPOUND

DESIGN

• Computer-aided drug design• Novel scaffolds, patent busting,

open FTO space• Strategy suited for project requirements

• Multistep synthesis of novel compounds, design and optimization

• Customized chemical libraries• Process optimization, parametrization

and scale-up

• Compound identity and purity

confirmation

• Water and residual solvents analysis

• Secure shared database

• Frequent face-to-face meetings

and reporting

• Challenging the hypotheses, evaluating current approach

• On-target in vitro potency and efficacy assessment

• Cell-based functional assays and proliferation studies

• ADME determination

• In vivo pharmacology

Validated hit compound

Preclinical candidate

Hit ID Hit to Lead

Data-Driven & Hypothesis-Driven Drug Discovery

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• Assay development• Screening library design• HTS/FBS/vHTS• Hit resynthesis & expansion

Hit identification & confirmation

• Computational chemistry/ Machine learning• Protein expression, production & crystallography • Biology• ADME• Medicinal chemistry

Structure/ligand-guided & rational drug design

AI enabled phenotypic screening

Leadoptimization

Addressing the challenges of Hit ID and Hit to Lead phases

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Assays developed

Screen run

Hits confirmed

Chemical routes scouted

Preliminary IP assessment made

Clinical tractability assessed

SAR established

LEAD COMPOUND

Our impact in Lead to Candidate

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CANDIDATE DRUG DELIVERED

Selectivity optimized

Potency optimized

ADME liabilities addressed

Mechanism of action elucidated

PK-PD profiles optimized

Pharmacokinetics optimized

IP secured

Formulations scouted

Route developed

Safety studies run

Our Drug Discovery Philosophy

Be fast & efficient

Be smart: make good use of diverse information

to support drug design

Holistically embrace target-based and phenotypic

approaches

Do not over-simplify: use adequately sophisticated

pharmacological models and high content screening

methods

Create an environment for innovation

Flexible and dynamic team structure

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COMPUTATIONAL CHEMIST

BIOLOGY TEAMLEADER

Senior Scientist

PROJECT MANAGERMedicinal Chemistry Leader

CHEMISTRY TEAM LEADER

Senior Scientist

BIOCHEMISTRY SUPPORT

SCREENING/PROFILING SUPPORT

ADME/PK SUPPORT

CHEMISTRY TEAM

Communication and reporting

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Daily communication as-needed

Weekly project reports typically as a PowerPoint presentation

Weekly or biweekly teleconferences between Project Manager and the Client

Face-to-face meetings as required

In order to facilitate more efficient project communication, we encourage direct scientist to scientist contact, simultaneously to discussions with the Project Leader.

Project Leader

Research Group

Selvita Database

CLIENT

Project Leader

Research Group

Partner DatabaseELN or securedata exchange

Broad and deep experience delivering advanced assets

PROJECTSHIT IDENTIFICATION

HIT TO LEAD

34

18

LEADOPTIMIZATION

CANDIDATESELECTION

PHASE I

9

10

6

2

1

1

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THERAPEUTIC AREA

ONCOLOGY

NEUROSCIENCES

RESPIRATORY

INFLAMMATION

METABOLIC DISEASE

DERMATOLOGY

OPTHALMOLOGY

ANTI-INFECTIVES

OTHER / RARE DISEASES

Experienced drug discovery team

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Over 150 years of combined experience in oncology, CNS, inflammation, metabolic diseases, anti-infectives,

neuroinflammation, pain, antibacterial, fungicides, respiratory, innate immunity

Thorough experience in kinases, GPCRs, proteinases, enzymes, transcription regulators, macromolecular interactions,

PROTACs

Tom Coulter

Integrated Drug Discovery Director

Wojciech Czardybon

Drug Discovery Consulting Director,

MedChem

Davide Franceschini

Drug Discovery, Biology

Przemyslaw Zawadzki

Director of Medicinal Chemistry

AnnaKarawajczyk

Head of Computational

Chemistry

Piotr Graczyk

Consulting Director

Chemistry

Cyprian Cukier

Head of Protein Crystallography

Laboratory

Jan Smagur

Cell and Molecular Biology Director

BoguslawLupa

Biochemistry Department

Director

SCIENTIFIC CAPABILITIES

Computational Support – main activities

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• Homology modeling

• Druggability analysis

• Analysis of the binding pocket

• Analysis of a family of the target protein

• Prediction of structural consequences upon a point

mutation

Target preparation and holistic analysis

• Computational chemistry/ Machine learning

• 3D pharmacophore or/and shape screening: classical and

with

AI implementation

• 2D pharmacophore/fingerprint/ substructure screening

• Docking

Ligand-based and structure-based virtual screeningTARGET PREPARATION

AND HOLISTIC ANALYSISLIGAND-BASED

AND STRUCTURE-BASED VIRTUAL SCREENING

Computational Support

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• Prediction of properties, their analysis and structure filtration

according to the need of the project

• Virtual library design meeting requirements of the project

• Triage

• Library enumeration and processing with incorporated synthetic

feasibility

• Application of structural filters to remove undesired groups

and toxicophores

• Molecular descriptor calculations used for SAR analysis

and compounds quality assurance

• Similarity and diversity analysis

• Identification of IP space

• AI based models for analysis and classification

of compounds according to the scope of the project

CheminformaticsCHEMINFORMATICS

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Screening assays & compound profiling

• Medium/high throughput mode

• 96/384/1536-well plate formats

• Recombinant cell lines (more than 200 cell lines)

• Various read-outs:

• End-point and continuous enzymatic assays

• Luminescence, Abs, FI, FP, FRET, TR-FRET, Alpha Technology

• Biochemical activity and biophysical binding assays

• Compound profiling (MoA, competitiveness etc.)

• Compound libraries screening in HTS mode

• In-house Compound Collection:

• Diverse compounds (160K cmpds)

• Fragments (1.5K)

• Focused custom libraries

Variable assay formats & detection modes• VARIABLE ASSAY FORMATS & DETECTION MODES

Medicinal Chemistry

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• 150 Chemists

• 50% PhDs

• 11 different nationalities

• 21% foreigners

• On average 8 years

industrial experience

• Stable organic growth

~20% y/y

• Oncology

• CNS

• Inflammation

• Respiratory

• Metabolic disease

• Anti-infectives

• One stop shop

strategy

• One location for all

IDD departments

• ELN implemented

• Strong IP and data

protection

• 11 fully equipped

chemistry modules

(~100m2 each)

• Capabilities for scale-up

up to 1kg

• Purification department

(including SFC)

• Analytical department

(LC-MS, SFC, NMR on-site)

• Over 50 satisfied partners

in 2019

• 95% collaborations based

on FTE model

• Several multiproject

collaborations

• Global presence –

US, Europe, Japan

RESOURCES OPERATIONS EQUIPMENTTHERAPEUTIC AREAS PARTNERSHIP

In vitro biochemical, biophysical

and cell-based assays

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Expertise with various classes of:

• enzymes e.g. as kinases, phosphatases, metabolic

enzymes, immuno-modulatory enzymes

• protein receptors e.g. GPCRs, nuclear receptors

Biochemical activity assays: end-point and continuous,

coupled

Biophysical binding assays: radioligand-based,

FTS, SPR, ITC, FP, MST

Functional cell-based assays:

• analysis of phosphorylation and de-

phosphorylation

• analysis of signal transduction

• protein biomarkers (Western Blot or ELISA assays)

Implementation

of multiple

biochemical,

biophysical

and cell-based

assays

to facilitate target

ID, validation

and in vitro

efficacy

assessment

Structural biology

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• Comprehensive gene-to-structure service

• Crystallization-grade proteins (E. coli, insect and

mammalian expression systems)

• Automated screening of up to 1200 crystallization

conditions using Crystal Gryphon, Art Robbins

Instruments)

• Monitoring of crystal growth using UV fluorescence

microscope (UVEX-p plate-scanning microscope, JANSi)

• Extensive crystal optimization (grid screening,

temperature, seeding etc.)

• Protein-ligand crystals via soaking or co-crystallization

• Diffraction measurements at synchrotron facilities in

Europe

• Structure determination using Molecular Replacement

and experimental phasing

• HIT VALIDATION / HIT-TO-LEAD DEVELOPMENT / LEAD OPTIMIZATION

ADME Capabilities

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PHYSICO-CHEMICAL PROFILING

• Kinetic Solubility• Thermodynamic

Solubility• Lipophilicity (LogD/LogP)• pKa determination

IN VITRO PERMEABILITY STUDIES

• Passive Transport Assessment• PAMPA GI, BBB

• Active Transport Assessment• Caco-2 Permeability• MDR1-MDCKII Permeability

IN VITRO METABOLISM STUDIES

• Microsomal stability• S9 Stability• Hepatocyte Stability• Plasma Stability• Metabolite Profiling and

Identification

IN VITRO BINDING STUDIES

• Plasma Protein Binding – Rapid Equilibrium Dialysis

• Plasma Protein Binding – High Sensitivity Binding Kit

• Tissue Binding – Rapid Equilibrium Dialysis

CYP STUDIES

• Inhibition of the cytochrome P450 isoform activity (IC50, screening assay)

Q-Exactive Plus Q-FT-HR-MS/MS (Thermo Fisher Scientific)

Sirius T3 (PION)

Bioanalytical Capabilities

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• Method Development/Transfer

• Method Verification

• Method Validation

• Qualitative Analysis

• Quantitative Analysis

Matrices: Plasma and Tissue Homogenates

State-of-the-art highly sensitive instrumentation

• Altis ESI/APCI TSQ (Thermo Fisher Scientific)

• Q-Exactive Plus Q-FT-HR-MS/MS (Thermo Fisher Scientific)

• LCMS-8050, ESI/APCI-QQQ (Shimadzu)

• LCMS-6470 ESI/APCI-QQQ (Agilent)

• AmaZon SL, ESI/APCI-IT (Bruker)

• AmaZon Speed ESI/APCI-IT (Bruker)

• Sirius T3 (PION)GMP/GLP compliant facility

In vivo preclinical pharmacology

PARTNERSTUDY TYPE SELVITA

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• DESIGN• COORDINATION

• MODEL SELECTION

• IN VIVO EXPERIMENT

• GENERAL ROUTINE ANALYSIS

IN VIVO PHASE WITHSPECIALIZED PRIVATE OR ACADEMIC INSTITUTIONS

Disease expertise: • CNS

(e.g. psychiatric diseases, neurodegeneration)

• Cancer(e.g. xeno and allo-grafts)

STUDY TYPE MOUSE RAT

Pharmacokinetic

Pharmacodynamic

• CUSTOMIZED ANALYSIS WITH PECULIAR TOOLS

• CONCLUSION• REPORTING

• DATA ANALYSIS

• DISCUSSION AND REPORTING

SELVITA

OUR TEAM SUCCESSFULLY DESIGNS, COORDINATES

AND ANALYZES DATA FROM STUDIES

PERFORMED IN ANIMALS

PK

PD

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