Human LIM domain kinase 1 (LIMK1), kinase domain; A Target Enabling Package

Loss of the translational repressor FMRP in fragile X syndrome causes upregulation of the type II BMP receptor BMPR2 and its non-canonical signalling via the kinase LIMK1. LIMK1 performs inhibitory phosphorylation on cofilin proteins blocking their actin-severing activity. Excessive BMPR2-LIMK1 activation was associated with dendritic spine and behavioural defects in animal models that could be rescued by BMPR2 knockdown or LIMK1 inhibition. Here we present a target enabling package for the therapeutic target LIMK1. We include crystal structures of BMPR2, LIMK1, LIMK2 and the LIMK1-cofilin complex, as well as multiple assays for small molecule inhibitor screening. Finally, we identify a series of allosteric LIMK1 inhibitors with promising potency and selectivity that may potentially allow the development of a safe drug for this chronic indication.