Target Enabling Packages (TEPs)

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Published June 2, 2017 | Version 5
Dataset Open

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

Description

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.

Notes

This document represents version 5 of the TEP datasheet and includes all updates on the project as of October 2018. For more information about TEPs and the TEP Programme, please visit https://thesgc.org/tep.

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Additional details

Related works

Is part of
https://www.thesgc.org/tep (URL)

Funding

Wellcome Trust
A UK Hub to Catalyse Open Target Discovery. 106169