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www.biofocus.com
Let your target define the compounds you screen
With the focus in R&D shifting to new target areas and novel approaches to existing targets, ensuring that the right compounds are
screened is essential.
Many companies have built up vast compound collections over time and routinely
turn to these when screening new targets.
Whilst this approach has some merit with
well-characterized protein targets, it tends
to be less successful in newer areas such as
protein-protein interactions (PPIs) or epigenetic targets, as a result of inherent bias
towards particular target families within
these collections.
Since its foundation, BioFocus has pioneered chemogenomic approaches to
designing compound libraries. To date,
more than 140 libraries containing over
110,000 individual purified compounds
have been made available to the drug
discovery community. By exploiting
similarities found across a gene family,
whilst ensuring there is scope to obtain
compounds with selectivity for individual members, highly successful
compound libraries generating immediate
structure-activity relationships (SAR) have
been designed. As the leader in this field
BioFocus is proud of its track record of success, with compounds from its SoftFocus®
libraries being the source of multiple
clinical candidates and client patents.1
Furthermore, a wealth of literature from
BioFocus’ clients highlights the positive
impact that screening SoftFocus libraries
has had upon their programs.2
Since 2000, BioFocus has developed
novel chemogenomic approaches to the
design of SoftFocus libraries directed
towards kinases, GPCRs, ion channels and
protease targets.1 Evolution of the BioFocus
design strategies has been continuous, as
new information about each target class is
discovered.
Not all target families are amenable to
chemogenomic library design, for example when there is insufficient knowledge
of the protein structure. In such cases
ligand-based approaches are adopted.
Examples of where these have been applied
successfully include the transient receptor potential (TRP) family of ion channels
and the design of allosteric modulators of
metabotropic glutamate receptors.
Most recently, BioFocus has initiated the
rational design of compound libraries in
two exciting new areas of research: proteinprotein interactions and epigenetics.
Protein-protein interactions
The likely success of inhibiting PPIs with
a small molecule is the subject of much
debate although, encouragingly, several
recent review articles show it can be done. 3
The topology of protein-protein interfaces
is generally very different to the active site
of receptors and enzymes and this may
explain why low hit rates have been found
with typical corporate collections. A classic
chemogenomic approach is not applicable
in this instance, so BioFocus has adopted a
protein epitope mimetic approach, focusing
on conserved secondary structural elements such as α-helices, β-strands, β-turns
etc. During early work it became apparent
that key peptide motifs exist that transcend
secondary structure. Pharmacophore models of these motifs were created and used
as the basis for designing conformationally
constrained scaffolds with the necessary
binding features and trajectories built in
(Figure 1). Moving forwards, attention has
turned towards the use of macrocycles for
disrupting PPIs and work is underway on
the design of macrocyclic libraries.
Epigenetics
Figure 1: Surface of MDM2 (3LBL.PDB) containing a Nutlin ligand (cyan) overlaid with a
p53 peptide (magenta, 1YCR.PDB).
Advances in the understanding of epigenetic processes have led to an explosion
of interest in this field. As in the kinase
field, there is a wealth of crystallographic
data available for several sub-families of
epigenetics targets, allowing both structure-based and chemogenomic approaches
to be applied to library design. BioFocus’
Figure 2A: Screenshot of a bromodomain epiRoadMap.
Figure 2B: A schematic of a bromodomain
indicating possible locations for library
scaffolds and appended R-groups.
initial focus has been on bromodomains and
histone methyl transferases. Computational
toolkits (epiRoadMaps, Figure 2A) have
been developed by BioFocus to allow the
comparison of multiple members of a
sub-family in order to identify conserved
regions within the binding site and regions
with greater structural variation. For library
design, the scaffold is targeted towards the
areas of highest conservation across the
family, and the substituent trajectories are
chosen to enable the substituent to enter
the areas of greater variability (Figure
2B). This design element generates a
gene-family targeted library that contains
compounds with the potential to selectively
interact with individual protein members.
Expanding further into epigenetics, the
design of libraries targeting lysine demethylases and chromodomains is underway.
Future developments in this area will
include other epigenetic sub-families, in
particular the ubiquitination enzymes.
The SoftFocus library philosophy
BioFocus’ philosophy is that the design
dictates the chemistry. As a result, synthesis can be complex and include defined
chirality. Substantial synthetic effort is
assigned to this to ensure robust routes are
developed, novel compounds are generated and the quality of design is high, all of
which set the BioFocus libraries apart from
those of many providers. The increased
investment in designing and synthesizing
the compound library is dwarfed by the
cost of prosecuting a new target and the
potential rewards more than outweigh the
initial cost.
Recently, BioFocus moved out of the nonexclusive library business and introduced a
new business concept of shared exclusivity.
Libraries are accessible to a maximum of
only ten privileged clients, thereby giving an
individual client greater prospects of securing intellectual property (IP) around any
screening hits. Whilst this model is relatively new, it has been well received in the
industry.
BioFocus will continue to develop innovative design approaches and make novel
compound libraries in the key research
areas of PPIs, epigenetics, kinases, and
receptors and channels. Support services
such as rapid re-synthesis of hits and the
production of small hit explosion arrays
to further scope out SAR, allow clients to
rapidly progress hits from initial screening
through hit-to-lead activities, accelerating
their drug discovery programs.
1. Sheppard, D. W. et al. The Design and
Application of Target-Focused Compound
Libraries. Combin. Chem. High-Throughput Screen
14 (6), 521–531 (2011)
2. Examples: (a) Mitchell, D.R. et al.
Mitogen-activated protein kinase-activated
protein kinase 2 (MAPKAP-K2) as an Antiinflammatory target: Discovery and in vivo
activity of selective pyrazolo[1,5-a]pyrimidine
inhibitors using a focused library and structurebased optimization approach. J. Med. Chem. 55
(15), 6700–6715 (2012) (b) Andrews, M.J.I.
et al. Discovery of a series of imidazopyrazine
small molecule inhibitors of the kinase
MAPKAPK5, that show activity using in vitro
and in vivo models of rheumatoid arthritis,
Bioorg. Med. Chem. Lett. 22 (6), 2266–2270
(2012)
3. (a) Fry, D. Small-molecule inhibitors of
protein-protein interactions: how to mimic
a protein partner. Curr. Pharm. Des. 18 (30),
4679-4684 (2012) (b) Berg, T. Small-molecule
inhibitors of protein-protein interactions.
Protein-Protein Complexes. 318–339 (2010)
(c) Thangudu, R. et al. Modulating proteinprotein interactions with small molecules: the
importance of binding hotspots. J. Mol. Biol.
415 (2), 443–453 (2012) (d) Thiel, P et al.
small molecule stabilization of protein-protein
interactions: an underestimated concept in
drug discovery. Angew. Chem. Int. Ed. 51 (9),
2012–2018 (2012)
Authors
Dr. Richard Hill and Dr. Jackie Macritchie.
Contact details
For information on BioFocus’ SoftFocus
subscription model, contact Richard Hill at
[email protected] or Jackie Macritchie
at [email protected].
BioFocus
Chesterford Research Park
Saffron Walden
Essex
CB10 1XL
United Kingdom
www.biofocus.com
About us
BioFocus provides integrated drug discovery that delivers pre-clinical drug candidates in all therapeutic
areas with strong capabilities in neurodegenerative diseases, inflammatory diseases and rare and
neglected diseases.
BioFocus has advanced and comprehensive drug discovery capabilities that are applied to client
projects to deliver targets, hits, leads and pre-clinical candidates. The company employs exceptionally
qualified and industry experienced scientists at its research centers in the UK and the Netherlands. For
more information, visit www.biofocus.com.
BioFocus has been a member of the Galapagos group of companies since 2005. www.glpg.com.
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