Biomedical Engineering Reference
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FIGURE 8.2 Activators of the VEGFR2 kinase and inhibitors of the Akt3, MAPKAPK2,
p38 -Src, and Pim1 kinases, as exemplified by 29 and the optimized analog 30 .
DNA amplification allowed identification of the active sequence. In terms of diver-
sity, scaffolds X represented various chain lengths (Scheme 8.5), whereas building
blocks Y, Z, and T ( 27 ) cover aliphatic, branched, aromatic, heteroaromatic,
- and
-amino acids, and turn inducers, with a large representation of unnatural amino acids
[46,47].
Screening of the library was conveniently performed in one test tube per target
using in vitro affinity selection. The authors reported the identification of activators
of the VEGFR2 kinase and inhibitors of the Akt3, MAPKAPK2, p38
-Src, and Pim1
kinases [48], as exemplified by 29 (Figure 8.2), which possesses IC 50 =
M
against the Src kinase and excellent selectivity against a panel of 44 kinases, including
related kinases such as Abl, Aurora A and B, RET, Blk, Fgr, Frk, Fyn, Hck, Lck, and
LynA and B. This is noteworthy in light of the difficulties in reaching selectivity for
that particular target. The authors tentatively attribute selectivity to library design,
which emphasizes rigid macrocyclic structures, and to the larger molecular size of
this class of inhibitors compared to classical ATP-competitive inhibitors. In this
case, macrocycles have the unique capacity to interact simultaneously with the ATP
binding pocket and reach less-conserved residues outside the ATP binding pocket.
In a subsequent study [49], the activity of macrocycle 29 was further refined to
provide analog 30 with IC 50 <
0.68
4 nM. Using molecular modeling, they demonstrated
that 30 behaves as a bisubstrate-competitive Src inhibitor with high potency and
exceptional selectivity, owing to interactions with both the ATP binding pocket and
the substrate-binding region. They demonstrated further that the level of peptide
substrate competition could be modulated to inhibit preferentially the phosphorylation
of strongly binding peptides over weaker substrates, opening the way to biasing the
signaling of the Src kinase. In the present case, the ability of this scaffold to overlap
with both binding pockets while retaining high affinity and high selectivity reflects
the ability of the macrocyclic structure to display distant and precisely oriented
pharmacophoric groups.
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