Biomedical Engineering Reference
In-Depth Information
Very recently, Philochem and ETH Zurich used a high-quality DNA-encoded
chemical library comprising 30,000 drug-like compounds to identify specific ligands
to the proinflammatory cytokine interleukin-2 (IL-2) (entry 23, Table 11.1) [66]. After
panning and decoding of the library, the isolated compounds exhibited affinity to the
target in the low-micromolar range (
K
D
=
M) and a complete and selective
inhibition of IL-2 activity in a T-cell proliferation assay (IC
50
=
2.5
32
M), without
any cytotoxicity to primary fibroblast cell cultures up to 128
M concentrations
[66]. Additionally, the binding mode of the newly discovered compound class was
confirmed by computational docking based on the crystal structure of IL-2 [66,121].
The docking revealed the 2-methyl-1
H
-indole moiety of 67 of 100 structurally related
compounds positioned in the same hydrophobic groove of the cytokine with a strong
propensity for binding aromatic structures [66,121].
In 2009, Praecis/GSK reported the use of high-throughput-sequencing techniques
for the decoding of very large DNA-encoded chemical libraries containing 7 million
and 800 million DNA-encoded compounds, respectively (see Section 11.2.2.1; entries
11 to 13, Table 11.1) [58]. Selection experiments yielded to the identification of
inhibitors against Aurora A and p38 MAP kinases with submicromolar potencies [58].
In 2010, Kleiner et al. described the first application of a DNA-templated library
for the de novo discovery of bioactive molecules (entry 18, Table 11.1) [77]. Selec-
tions using a 13,824-member macrocycle library against 36 different target proteins
enabled the isolation of novel classes of kinases modulators [77]. Compounds selected
included ATP-competitive Src inhibitors (with IC
50
as potent as 680 and 960 nM),
p38
M) as well as VEGFR2 activators (up to
300% activity enhancement upon treatment with a 100
-MAPKAP2 cascade inhibitor (11
M compound) [77].
DNA-encoded chemical libraries have also been successfully used to convert
previously discovered lead structures into new derivatives with enhanced potency
and specificity. Indeed, benzamidine-based dual- and single-pharmacophore lead
optimization (affinity maturation) libraries allowed the isolation of up to over 10,000-
fold improved trypsin inhibitor, with IC
50
in the single-digit nanomolar range and
excellent selectivity with respect to other related serine proteases (entries 4 and 19,
Table 11.1) [62,95]. Eventually, rapid and efficient DNA-encoded affinity maturation
strategies may be alternative (or complementary) to conventional medicinal chemistry
approaches to the optimization of compounds hits.
11.5 DNA-ENCODED CHEMICAL LIBRARIES: PROSPECTS
AND OUTLOOK
The appeal of DNA-encoded chemical library technology is indubitably due to the
stunning sensitivity of DNA encoding/decoding and the unrivalled opportunity to
generate ready-to-screen chemical libraries comprising thousands to millions of small
organic molecules in a single test tube [54,55,58,90,96].
A DNA-encoded library expands the realm of selection approaches, so far used
exclusively for the efficient isolation of high-affinity-binding polypeptides, to the
world of small organic molecules. En masse interrogation of chemical libraries by
