Integrated fragment-based drug design to unlock your disease target

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Diverse Fragment Collection

High Quality Protein Supply

Are you looking to identify tractable chemical matter?

Have you identified an interesting and challenging biological target?

High Quality Protein SupplyDomainex’s highly experienced Protein Sciences team can generate crystallography-grade proteins in multi-mg quantities using E. coli and baculoviral-infected insect cell expression systems.

Our scientists can utilize standard bioinformatics/literature-informed approaches or Domainex’s proprietary technology, Combinatorial Domain Hunting (CDH).

• CDH can quickly identify soluble, highlyexpressible protein constructs of drugtarget proteins

• To find out more about CDH please requesta copy of our separate CDH brochure or visitwww.domainex.co.uk

Diverse Fragment CollectionAlong with its strategic partner SpiroChem, Domainex has curated a diverse collection of fragments.

• Multi-parameter scoring function usedto select compounds

• Molecular fingerprints used and compared withChEMBL fragments to ensure good coverageof bioactive space

• Access to Spirochem fragments providesnovel starting points

• All compounds soluble at 1 mM in 1% DMSO

Fragment Screening X-ray Crystallography & SBDD

What is FragmentBuilder?FragmentBuilder is Domainex’s fragment-based drug discovery (FBDD) platform. Starting from a target gene, Domainex deploys its expertise in Protein Science, Assay Biology and Medicinal Chemistry to discover tractable, patentable leads cost-effectively.

Why Choose FragmentBuilder?

Fragment ScreeningAt the heart of the platform is screening of fragments by MicroScale Thermophoresis (MST, Nanotemper Technologies GmbH). This capillary-based, homogenous technology is able to quantify even weak binding events in a solution-based manner. The Domainex fragment collection can be screened in a matter of a few days to determine initial Kd values of fragment hits. Domainex has alternative screening methods available if required, such as HTRF, DSF and direct-binding mass spectrometry.

MST Advantages Over Alternative Methods • Minimal assay development

• Little protein required

• Solution-based, so no immobilization

• Measure up to quaternary biological systems

• Capture orthosteric and allosteric binders

• Sensitive across the nM-mM range

• A high throughput technique

• Eliminates false positives early

X-ray Crystallography & SBDDDomainex has the expertise to undertake crystal screens and through its access to the synchrotron at Diamond Light Source (Oxfordshire, UK) can obtain high-resolution structures of fragment hits bound to target proteins. These can then be used by computational and medicinal chemists at Domainex to guide an efficient fragment elaboration process.

• Domainex has a proven track record in FBDD

• Access to Domainex’s exclusive library:

– Expertly selected

– Diverse with good coverage of bioactive fragment space

– Includes innovative SpiroChem fragments (greater complexity and 3D character)

• Choice of primary screening methods available

• Domainex can generate high resolution crystal structures of bound fragments

• Modules can be accessed on their own or together to form a fully integrated service

Rapid Elaboration of Fragment Hits

Activity Confirmation in Biochemical and

Cellular Assays

Why Choose FragmentBuilder?

Fragment SAR & Rapid Elaboration of Fragment HitsSee overleaf for a description of how Domainex medicinal and computational chemists can combine searches of its curated databases of existing fragments- and lead-like compounds and combine this with the synthesis of new, more potent compounds.

Orthogonal & Functional TestingThe Domainex Assay Biology team can establish competition assays to determine the mechanism of binding of identified screening hits and can use a range of orthogonal tests including:

• Saturation Transfer Difference (STD) – NMR

• Surface Plasmon Resonance (SPR)

• Differential Scanning Fluorimetry (DSF)

Once the project has progressed, the team can run cellular assays to further profile novel compounds received from the medicinal chemistry team. In parallel, in vitro ADME assays are run on the most promising compounds to help identify tractable leads.

Medicinal and Computational Chemistry Domainex has a team of highly skilled chemists experienced in FBDD who will optimise your fragment hits. Domainex and Spirochem chemists understand the chemistry around their fragments and together can quickly synthesize analogues/elaborated compounds. Domainex has developed an efficient process for fragment hit expansion:

FACE (Fragment Analogues for Chemical Evaluation): ~200,000 commercially-available compounds that meet our fragment criteria.

LE = Ligand Efficiency

NICE (Number of Interesting Chemical Entities): ~2 million lead-like commercially-available compounds

Focus on ‘growing’ the fragments to increase protency.

• Lead-like compounds sourced from Domainex’s NICE database

• Medicinal chemists deployed to design and produce de novo compounds

• Parallel chemistry

• Iterative screening

Aim to identify related fragments with LE ≥ 0.4.

• Source and screen lead-like compounds from the Domainex FACE database

Fragment Hits

LE≥0.4

LE≥0.4

LE<0.4

The Process

Design andChemicalSynthesis

FragmentBuilder Output

Within 6 months Domainex will identify 1 or more hit series with:

• Potency in the low micromolar range• LE ≥0.35• Good physchem. properties• Structural data at good resolution • Novelty

CompoundTesting

Analogue Sourcing• FACE Database• NICE Database

FragmentLibrary

Screening

X-RayCrystallography

Hit Identification

and Confirmation

DomainexFragment

Library

AssayDevelopment

ProteinProduction

About DomainexDomainex is a fully integrated drug discovery service company based near Cambridge, UK serving pharmaceutical, biotechnology, academic and patient foundations globally. Domainex’s drug discovery service business was established in 2001 and since that time has continued to expand to serve a wider range of clients across the world including UCB, FORMA Therapeutics, St George’s University, The Institute of Cancer Research and Auspherix. Our expertise and commitment to providing high quality services has resulted in a strong success record in drug discovery, delivering an average of one candidate drug every year for the past six years.

If you would like to know more about Domainex’s discovery services, or speak to us regarding your own drug discovery needs, please contact us at: enquiries@domainex.co.uk

Meet the Team

www.domainex.co.uk

Dr. Thomas Mander MBAChief Operating Officertom.mander@domainex.co.ukTel: +44 (0) 7584 578024Direct: +44 (0) 1223 743174

Domainex Chesterford Research ParkLittle Chesterford, CambridgeCB10 1XL

Dr Gary Newton, Principal Research Leader – ChemistryGary joined Domainex in 2004 and has extensive experience working on a range of targets in all phases from hit identification through to pre-clinical candidate nomination. During his time at Domainex, Gary has been the principal architect of the design of three candidate drugs, one of which originated from a fragment hit. Gary was a key member of the team who curated the Domainex fragment library and continues to be involved in the ongoing process of updating and reviewing the library.

Dr Stefanie Reich, Group Leader – Protein Science Stefanie joined Domainex in 2006 and has successfully managed over 50 internal and client-based projects, using a range of techniques, including gene design, molecular biology, protein expression and purification and structural analysis. Stefanie was a key member of the team that developed Combinatorial Domain Hunting (CDH) and is an expert in its application to difficult protein expression problems.

Dr Jana Wolf, Team Leader – Assay Biology Jana joined Domainex in 2014 and has worked on a wide variety of targets including kinases, epigenetic targets and protein-protein interactions. She was responsible for establishing Microscale Thermophoresis (MST) at Domainex and has since used the technique to run successful fragment screens against a range of targets for multiple clients.