Dipartimento di Biotecnologie, Chimica e Farmacia (Dipartimento di Eccellenza 2018-2022), via A. Moro 2, I-53100 Siena, Italy.
Eur J Med Chem. 2018 Jul 15;155:445-458. doi: 10.1016/j.ejmech.2018.06.016. Epub 2018 Jun 8.
LIM kinases are involved in various pathophysiological processes that depend on actin organization. Alteration of microtubule dynamics by LIMK dysregulation is in fact related to tumor progression and metastasis, viral infection, and ocular diseases, such as glaucoma. As a consequence, many efforts have been done in recent years to rationally design small molecules able to inhibit LIMK activity selectively, without affecting other kinases. As a result, compounds optimized in terms of binding affinity and pharmacokinetic parameters have been discovered, that however failed to access clinical trials. In this review, a comprehensive survey of recent LIMK inhibitors is reported, together with SAR considerations and optimization processes.
LIM 激酶参与各种依赖于肌动蛋白组织的病理生理过程。LIMK 失调引起的微管动力学改变实际上与肿瘤进展和转移、病毒感染以及青光眼等眼部疾病有关。因此，近年来，人们做出了许多努力，旨在合理设计能够选择性抑制 LIMK 活性而不影响其他激酶的小分子。因此，已经发现了在结合亲和力和药代动力学参数方面进行了优化的化合物，但它们未能进入临床试验。在这篇综述中，报道了最近的 LIMK 抑制剂的全面调查，以及 SAR 考虑因素和优化过程。
