发现新型吡唑并[1,5-a]嘧啶衍生物作为选择性 ROCK2 抑制剂，具有抗乳腺癌迁移和侵袭活性。
Discovery of novel pyrazolo[1,5-a]pyrimidine derivatives as selective ROCK2 inhibitors with anti-breast cancer migration and invasion activities.
发表日期：2024 Aug 02
作者：
Zhi Cao, Xiujian Wei, Shuming Xing, Jiahao Zhang, Shuqi Wang, Lingfeng Yue, Jiahe Zhang, Nan Jiang, Xin Zhai
来源：
BIOORGANIC CHEMISTRY
摘要：
Rho 相关卷曲螺旋激酶 (ROCK) 参与调节肌动蛋白细胞骨架的多种细胞活动，例如细胞形态、粘附和迁移。抑制ROCK是抑制乳腺癌转移的可行策略。本文以Belumosudil为基础，设计并合成了一系列吡唑并[1,5-a]嘧啶衍生物作为选择性ROCK2抑制剂。通过对 SAR 的系统研究，哌嗪类似物 7u 被确定具有最佳的 ROCK2 抑制活性 (IC50 = 36.8 nM)，并且比异构体蛋白 ROCK1 具有优异的选择性（> 250 倍）。有趣的是，用 7u 处理后，MDA-MB-231 细胞骨架的排列受到影响，并伴随着形态的改变。此外，细胞划痕和transwell实验表明7u以剂量依赖性方式抑制MDA-MB-231细胞迁移和侵袭。最终，7u 与 ROCK2 的结合模型很好地解释了 7u 作为一种有前途的 ROCK2 抑制剂的优越活性，并在乳腺癌转移治疗中具有潜在的应用。版权所有 © 2024 Elsevier Inc. 保留所有权利。
Rho-associated coiled-coil kinase (ROCK) is involved in multiple cellular activities regulating the actin cytoskeleton, such as cell morphology, adhesion, and migration. The inhibition of ROCK is a feasible strategy to suppress breast cancer metastasis. Herein, based on Belumosudil, a series of pyrazolo[1,5-a]pyrimidine derivatives as selective ROCK2 inhibitors were designed and synthesized. Through systematic investigation of SARs, the piperazine analog 7u was identified with optimum ROCK2 inhibitory activity (IC50 = 36.8 nM) and excellent selectivity over the isoform protein ROCK1 (>250-fold). Intriguingly, upon treatment with 7u, the arrangement of the MDA-MB-231 cytoskeleton was affected accompanied by the alteration of morphology. Furthermore, cell scratch and transwell assays indicated that 7u inhibited MDA-MB-231 cell migration and invasion in a dose-dependent manner. Ultimately, the binding model of 7u with ROCK2 well accounted for the superior activities of 7u as a promising ROCK2 inhibitor with the potential application in breast cancer metastasis treatment.Copyright © 2024 Elsevier Inc. All rights reserved.