C.E.Allen
et al.
(2013).
Synthesis and evaluation of heteroaryl substituted diazaspirocycles as scaffolds to probe the ATP-binding site of protein kinases.
Bioorg Med Chem Lett,
21,
5707-5724.
PubMed id: 23920481
DOI: 10.1016/j.bmc.2013.07.021
With the success of protein kinase inhibitors as drugs to target cancer, there
is a continued need for new kinase inhibitor scaffolds. We have investigated the
synthesis and kinase inhibition of new heteroaryl-substituted diazaspirocyclic
compounds that mimic ATP. Versatile syntheses of substituted diazaspirocycles
through ring-closing metathesis were demonstrated. Diazaspirocycles directly
linked to heteroaromatic hinge binder groups provided ligand efficient
inhibitors of multiple kinases, suitable as starting points for further
optimization. The binding modes of representative diazaspirocyclic motifs were
confirmed by protein crystallography. Selectivity profiles were influenced by
the hinge binder group and the interactions of basic nitrogen atoms in the
scaffold with acidic side-chains of residues in the ATP pocket. The introduction
of more complex substitution to the diazaspirocycles increased potency and
varied the selectivity profiles of these initial hits through engagement of the
P-loop and changes to the spirocycle conformation, demonstrating the potential
of these core scaffolds for future application to kinase inhibitor discovery.
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