Xie Yuting, Yue Lin, Shi Yaojie, Su Xingping, Gan Cailing, Liu Hongyao, Xue Taixiong, Ye Tinghong
Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
J Med Chem. 2023 Apr 13;66(7):4342-4360. doi: 10.1021/acs.jmedchem.2c01753. Epub 2023 Mar 20.
Rho-associated coiled-coil-containing kinases (ROCKs), serine/threonine protein kinases, were initially identified as downstream targets of the small GTP-binding protein Rho. Pulmonary fibrosis (PF) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Interestingly, ROCK activation has been demonstrated in PF patients and in animal PF models, making it a promising target for PF treatment. Many ROCK inhibitors have been discovered, and four of these have been approved for clinical use; however, no ROCK inhibitors are approved for the treatment of PF patients. In this article, we describe ROCK signaling pathways and the structure-activity relationship, potency, selectivity, binding modes, pharmacokinetics (PKs), biological functions, and recently reported inhibitors of ROCKs in the context of PF. We will also focus our attention on the challenges to be addressed when targeting ROCKs and discuss the strategy of ROCK inhibitor use in the treatment of PF.
Rho相关卷曲螺旋结构域蛋白激酶（ROCKs）是丝氨酸/苏氨酸蛋白激酶，最初被鉴定为小GTP结合蛋白Rho的下游靶点。肺纤维化（PF）是一种致命疾病，治疗选择有限，预后尤其不佳。有趣的是，ROCK激活已在PF患者和动物PF模型中得到证实，这使其成为PF治疗的一个有前景的靶点。已经发现了许多ROCK抑制剂，其中四种已被批准用于临床；然而，尚无ROCK抑制剂被批准用于治疗PF患者。在本文中，我们描述了ROCK信号通路以及在PF背景下ROCK的构效关系、效力、选择性、结合模式、药代动力学（PKs）、生物学功能和最近报道的抑制剂。我们还将关注靶向ROCK时需要解决的挑战，并讨论ROCK抑制剂在PF治疗中的使用策略。
