956
E. R. Wood et al. / Bioorg. Med. Chem. Lett. 14 (2004) 953–957
Figure 5. Kinase enzyme inhibition results against a representative set
of kinase enzyme assays. *Denotes maximum concentration tested,
not IC50 value determined.
In conclusion, we have discovered potent TrkA kinase
inhibitors in the oxindole series that are significantly
more selective than the staurosporine analogue(s)
reported in pre-clinical studies and clinical trials. We
included synthetic details, kinase enzyme data for trkA
plus representative kinase selectivity data, SAR and a
proposed binding mode in the ATP pocket of the kinase
catalytic region. It is also noteworthy that these com-
pounds are significantly more selective than published
trkA inhibitors (Staurosporines and Tyrphostins).
These compounds may offer the scientific community
useful target validation and signaling tools. Further
biological evaluation of these compounds is necessary to
determine if the TrkA activity is sufficient to achieve
anti-cancer effects.
Figure 4. Structure overlap of 1, 3, and 6.
4
suggests that the 7-position nitrogen is not the H-bond
acceptor in the hinge region since a large reduction in
potency would be expected with the removal of this key
interaction. Further SAR can be derived with the
potency and selectivity of 5, suggesting that there may
be multiple binding modes possible within the oxindole
and azaoxindole series.
The homologation of the linker between the benzylidene
aryl ring and the oxindole scaffold provides further
SAR and unique inhibitors of TrkA. While GW8510 is
not selective between TrkA and CDK2, removal of
fused ring substituents from the oxindole portion of the
molecule seemed to greatly reduce the inhibitory activity
of CDK2, while very little reduction in activity for TrkA
was observed. Reversing the connectivity of the sulfon-
amide, as in 6, afforded nearly 10,000-fold improvement
in selectivity. Other substituents that confer potency for
TrkA inhibition are phthalimide, 3-sulfonamide, and a
Acknowledgements
Screening data was provided by the GSK Assay Devel-
opment and Compound Profiling Group. The trkA
enzyme was expressed and purified by Margaret Karow
and Xiaodong Yang at Regeneron Pharmaceuticals,
Inc., 777 Old Saw Mill Rd, Tarrytown, NY 10591.
Wilson B. Knight and Stephen V. Frye supplied
guidance and support.
4
-triazole shown by 7, 8, and 9.
To provide some insights for potential binding modes,
, 3, and 6 were over-layed by aligning the oxindole
1
rings (Fig. 4). The substituted vinyl aniline and benzyli-
dene groups seem to fit the ATP binding pocket with a
Z-isomer configuration orientated toward the solvent
interface. While other binding modes are feasible, this
binding mode can accommodate the diversity of groups
that are tolerated in the 3- and 4-position of the term-
inal aryl ring. The available crystal structure inform-
ation can explain how to reduce CDK2 activity,19 but the
increase in TrkA inhibition activity remains empirical.
References and notes
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5
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