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.

脆性X综合征（fragile X syndrome）中，翻译抑制因子FMRP的缺失会导致II型骨形态发生蛋白受体BMPR2（type II BMP receptor BMPR2）的表达上调，以及其通过激酶LIMK1（LIMK1）介导的非经典信号通路激活。LIMK1可对丝切蛋白cofilin进行抑制性磷酸化修饰，阻断其肌动蛋白切割活性。过度激活的BMPR2-LIMK1通路与动物模型中的树突棘异常及行为缺陷相关，该类缺陷可通过敲低BMPR2或抑制LIMK1得到挽救。本研究针对治疗靶点LIMK1开发了一套靶点赋能套装（target enabling package），其中包含BMPR2、LIMK1、LIMK2以及LIMK1-丝切蛋白复合物的晶体结构，同时配套多种用于小分子抑制剂筛选的实验方法。最后，本研究筛选得到一系列变构LIMK1抑制剂，其活性与选择性均表现优异，有望为该慢性适应症开发安全有效的治疗药物。