Staurosporine-Derived
Inhibitors Broaden the Scope
of Analog-Sensitive Kinase Technology
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Abstract
Analog-sensitive (AS) kinase technology
is a powerful approach
for studying phospho-signaling pathways in diverse organisms and physiological
processes. The key feature of this technique is that a kinase-of-interest
can be mutated to sensitize it to inhibitor analogs that do not target
wild-type (WT) kinases. In theory, this enables specific inhibition
of any kinase in cells and in mouse models of human disease. Typically,
these inhibitors are identified from a small library of molecules
based on the pyrazolopyrimidine (PP) scaffold. However, we recently
identified a subset of native human kinases, including the Ephrin
A kinase family, that are sensitive to commonly used PP inhibitors.
In an effort to develop a bioorthogonal AS-kinase inhibitor and to
extend this technique to PP-sensitive kinases, we sought an alternative
inhibitor scaffold. Here we report the structure-based design of synthetically
tractable, potent, and extremely selective AS-kinase inhibitors based
on the natural product staurosporine. We demonstrate that these molecules,
termed staralogs, potently target AS kinases in cells, and we employ
X-ray crystallography to elucidate their mechanism of efficacy. Finally,
we demonstrate that staralogs target AS mutants of PP-sensitive kinases
at concentrations where there is little to no inhibition of native
human kinases. Thus, staralogs represent a new class of AS-kinase
inhibitors and a core component of the chemical genetic tool kit for
probing kinase-signaling pathways