Repurposing of the RIPK1-Selective Benzo[1,4]oxazepin-4-one Scaffold for the Development of a Type III LIMK1/2 Inhibitor

Benzoxazepinones
have been extensively studied as exclusively
selective
RIP kinase 1 inhibitors. This scaffold binds to an allosteric pocket
created by an αC-out/DFG-out conformation. This inactive conformation
results in a large expansion of the kinase back pocket, a conformation
that has also been reported for LIM kinases. Scaffold hopping is common
in the design of orthosteric kinase inhibitors but has not been explored
in the design of allosteric inhibitors, mainly due to the typically
exclusive selectivity of type III inhibitors. Here, we hypothesized
that the shared structural properties of LIMKs and RIPKs could lead
to novel type III LIMK inhibitors using the benzoxazepinone scaffold.
We report the discovery of a novel LIMK1/2 inhibitor that relies on
this scaffold-based approach. The discovered compound 10 showed low nanomolar potency on LIMK1/2 and exceptional selectivity,
as confirmed by a comprehensive selectivity panel with residual RIPK
activity as the only off-target. The study provides one of the few
examples for scaffold hopping for allosteric inhibitors, which are
usually associated with exclusive target selectivity.