First-in-Human Study of the Safety of AR-13503 Sustained Release Intravitreal Implant in Subjects With Neovascular Age-Related Macular Degeneration (nAMD) and Subjects With Diabetic Macular Edema (DME)

First-in-Human Study of the Safety of AR-13503 Sustained Release Intravitreal Implant in Subjects with Neovascular Age-Related Macular Degeneration (nAMD) and Subjects with Diabetic Macular Edema (DME)

开始日期2019-06-24

申办/合作机构

Aerie Pharmaceuticals, Inc.

100 项与 PKC x ROCK 相关的临床结果

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100 项与 PKC x ROCK 相关的转化医学

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0 项与 PKC x ROCK 相关的专利（医药）

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项与 PKC x ROCK 相关的文献（医药）

2024-05-01·Biomolecules & Therapeutics

Effect of Kaempferol on Modulation of Vascular Contractility Mainly through PKC and CPI-17 Inactivation

Article

作者: Min, Young Sil ; Yoon, Hyuk-Jun ; Sohn, Uy Dong ; Bang, Joon Seok ; Jin, Fanxue ; Je, Hyun Dong ; Moon, Heui Woong

In this study, we investigated the efficacy of kaempferol (a flavonoid found in plants and plant-derived foods such as kale, beans, tea, spinach and broccoli) on vascular contractibility and aimed to clarify the detailed mechanism underlying the relaxation. Isometric contractions of divested muscles were stored and linked with western blot analysis which was carried out to estimate the phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and phosphorylation-dependent inhibitory protein for myosin phosphatase (CPI-17) and to estimate the effect of kaempferol on the RhoA/ROCK/CPI-17 pathway. Kaempferol conspicuously impeded phorbol ester-, fluoride- and a thromboxane mimetic-derived contractions regardless of endothelial nitric oxide synthesis, indicating its direct effect on smooth muscles. It also conspicuously impeded the fluoride-derived elevation in phospho-MYPT1 rather than phospho-CPI-17 levels and phorbol 12,13-dibutyrate-derived increase in phospho-CPI-17 and phospho-ERK1/2 levels, suggesting the depression of PKC and MEK activities and subsequent phosphorylation of CPI-17 and ERK1/2. Taken together, these outcomes suggest that kaempferol-derived relaxation incorporates myosin phosphatase retrieval and calcium desensitization, which appear to be modulated by CPI-17 dephosphorylation mainly through PKC inactivation.

2024-03-01·Microvascular Research

Role of protein kinase D1 in vasoconstriction and haemodynamics in rats

Article

作者: Oku, Shinya ; Sawada, Yuri ; Mizuno, Yusuke ; Goto, Takahisa ; Sugawara, Yoh

AIMSProtein kinase D (PKD), once considered an effector of protein kinase C (PKC), now plays many pathophysiological roles in various tissues. However, little is known about role of PKD in vascular function. We investigated the role of PKD in contraction of rat aorta and human aortic smooth muscle cells (HASMCs) and in haemodynamics in rats.METHODS AND RESULTSIsometric tension of rat aortic was measured to examine norepinephrine-induced contraction in the presence of PKD, PKC and Rho-kinase inhibitors. Phosphorylation of PKD1, myosin targeting subunit-1 (MYPT1), myosin light chain (MLC), CPI-17 and heat-shock protein 27 (HSP27), and actin polymerization were measured in the aorta. Phosphorylation of MYPT1 and MLC was also measured in HASMCs knocked down with specific siRNAs of PKD 1, 2 and 3. Intracellular calcium concentrations and cell shortening were measured in HASMCs. Norepinephrine-induced aortic contraction was accompanied by increased phosphorylation of PKD1, MYPT1 and MLC and actin polymerization, all of which were attenuated with PKD inhibitor CRT0066101. PKD1 phosphorylation was not inhibited by PKC inhibitor, chelerythrine or Rho kinase inhibitor, fasudil. In HASMCs, the phosphorylation of MYPT1 and MLC was attenuated by PKD1, but not PKD2, 3 knockdown. In HASMCs, CRT0066101 inhibited norepinephrine-induced cell shortening without affecting calcium concentration. Administration of CRT0066101 decreased systemic vascular resistance and blood pressure without affecting cardiac output in rats.CONCLUSIONSPKD1 may play roles in aorta contraction and haemodynamics via phosphorylation of MYPT1 and actin polymerization in a calcium-independent manner.

2024-03-01·Journal of Cell Science

MUC13 negatively regulates tight junction proteins and intestinal epithelial barrier integrity via protein kinase C

Article

作者: van Putten, Jos P M ; Passchier, Elsemieke ; Su, Jinyi ; Wu, Wei ; Stapels, Daphne A C ; Westendorp, Bart ; Segui-Perez, Celia ; Ma, Ziliang ; Strijbis, Karin ; Wubbolts, Richard W

ABSTRACTGlycosylated mucin proteins contribute to the essential barrier function of the intestinal epithelium. The transmembrane mucin MUC13 is an abundant intestinal glycoprotein with important functions for mucosal maintenance that are not yet completely understood. We demonstrate that in human intestinal epithelial monolayers, MUC13 localized to both the apical surface and the tight junction (TJ) region on the lateral membrane. MUC13 deletion resulted in increased transepithelial resistance (TEER) and reduced translocation of small solutes. TEER buildup in ΔMUC13 cells could be prevented by addition of MLCK, ROCK or protein kinase C (PKC) inhibitors. The levels of TJ proteins including claudins and occludin were highly increased in membrane fractions of MUC13 knockout cells. Removal of the MUC13 cytoplasmic tail (CT) also altered TJ composition but did not affect TEER. The increased buildup of TJ complexes in ΔMUC13 and MUC13-ΔCT cells was dependent on PKC. The responsible PKC member might be PKCδ (or PRKCD) based on elevated protein levels in the absence of full-length MUC13. Our results demonstrate for the first time that a mucin protein can negatively regulate TJ function and stimulate intestinal barrier permeability.

项与 PKC x ROCK 相关的新闻（医药）

2023-08-11

·药渡Daily

浅谈ROCKs抑制剂研究进展

关键词ROCKs；研究进展；贝舒地尔ROCKs是Rho相关卷曲螺旋形成蛋白激酶，又称Rho激酶，属于丝氨酸-苏氨酸激酶家族，是小GTP结合蛋白RhoA的重要下游效应器。ROCKs大致分为三个部分：N-末端、中央螺旋卷曲区域、C-末端，其中N-末端主要包含激酶结构域，中央螺旋卷曲区域包含Rho-结合域（RBD），C-末端包含PH域和半胱氨酸富含区域（CRD）。研究发现，由于ROCKs的C-末端可作为N-末端激酶域的自动调节抑制剂，ROCKs通常情况下处于非激活状态，只有在一定条件下才可被激活。据日本名古屋大学Amano，M教授的研究，ROCKs主要通过以下三种途径激活：RhoA与ROCKs上Rho-结合域（RBD）结合，使C-末端RBD-PH区域抑制状态得以释放，从而导致激酶域的“开放”，激活ROCKs；这种开放的构象还可以通过花生四烯酸结合到PH结构域来实现；颗粒酶B或切东酶-3通过裂解C-末端也可以激活ROCKs。此外，ROCKs还能通过蛋白低聚反应使N-末端发生转磷酸反应被激活。激活的ROCKs通过作用于其下游靶点介导细胞骨架的改变。目前已知的ROCKs的作用靶点主要有MLCP，LIM激酶和ERM蛋白质等。通过磷酸化这些靶点蛋白，从而导致细胞收缩、内皮功能破坏、血管平滑肌细胞增殖、炎细胞浸润、动脉粥样硬化形成。多款ROCKs抑制剂获批上市目前，全球已批准多款ROCKs抑制剂，详见下表。已获批的ROCKs抑制剂选择性低，作用靶点多为ROCK1和ROCK2。ROCKs抑制剂获批的适应症多样，涉及脑血管痉挛及引起的脑缺血症状、青光眼、慢性移植物抗宿主病。全球已批准的ROCKs抑制剂来源：药渡数据库然而，我国已获批的ROCKs抑制剂较少，仅有盐酸法舒地尔、甲磺酸法舒地尔和贝舒地尔。其中贝舒地尔于今年8月在国内正式获批，用于治疗慢性移植物抗宿主病（cGVHD）。在研ROCKs抑制剂研究进展此外，目前全球还有多款在研ROCKs抑制剂，详见下表。在研ROCKs抑制剂作用靶点同样选择性不高，大多针对ROCK1和ROCK2，以及其他靶点，适应症主要为纤维化、青光眼等。全球部分在研ROCKs抑制剂来源：药渡数据库TQ05105TQ05105是一个全新具有国家自主知识产权的小分子JAK1/2、ROCK1/2靶向抑制剂。已公布的临床研究数据显示：TQ05105对糖皮质激素相关或依赖性慢性移植物抗宿主病有很好的疗效，最佳缓解率达86%。而且与国际上市JAK2抑制剂进行比较，TQ05105的总体缓解率、疗效、各脏器功能特别是肺纤维化均显示出很好的结果。VVN539VVN539是维眸生物自主研发的新一代、具有双靶点机制的降眼压药物，直接作用于眼部小梁网，增加房水外流，从而达到降低眼压的效果。在临床前动物模型中，VVN539表现出优异的降眼压效果，有望成为具有全球竞争力的眼科创新药。今年6月，VVN539针对开角型青光眼或高眼压患者的美国2期临床达到主要研究终点。数据显示：与溶媒组相比，0.04% VVN539剂量组在所有时间点均达到了统计学显著性及临床显著性，眼压降压幅度约为5~6 mmHg。0.02% VVN539剂量组在大多数时间点相较于溶媒组也达到了具有统计学意义的眼压下降。此外，研究中未观察到显著的与治疗相关的不良事件。OPL-0401OPL-0401是Valo Health基于其Opal计算系统设计研发出的一种小分子Rho激酶（ROCK 1/2）抑制剂，因其独特的理化性质可作为口服治疗选择，是非增殖性糖尿病视网膜病变患者潜在的“First-in-class”口服疗法选择。RXC007RXC007是一种新一代选择性ROCK2抑制剂，目前正在特发性肺纤维化的2a期研究中进行评估，预计2024年第一季度将获得最新数据。今年2月，美国Jounce Therapeutics宣布将与英国Redx Pharma进行反向合并，而合并后的最高优先事项将是开发RXC007。TDI-01TDI-01是一款高选择性ROCK2抑制剂，在美国1期临床研究和国内的人种桥接实验中表现出了良好的安全性结果和药代动力学性质，被开发用于治疗特发性肺纤维化、尘肺病、GVHD、抗新冠病毒。2021年2月，泰德制药就TDI01与美国Graviton Biosciences达成海外授权合作协议，交易总值达5.175亿美元。AR-13503AR-13503是一款Rho激酶和蛋白激酶C的专有小分子抑制剂。临床前研究表明， AR-13503可能抑制血管生成，保留视网膜屏障，减少视网膜纤维化的视网膜疾病，同时可能减少治疗负担与更频繁的玻璃体内注射。总结ROCKs抑制剂被开发用于治疗多种疾病，目前已在预防和改善蛛网膜下腔出血术后的脑血管痉孪及其引起的脑缺血症状、降低高眼压、治疗慢性移植物抗宿主病有所收获。而且，还有多款在研ROCKs抑制剂被开发用于治疗纤维化疾病、糖尿病视网膜病变等。我国药企，如正大天晴、维眸生物、泰德制药等也积极布局ROCKs抑制剂领域，其中泰德制药的ROCK2抑制剂TDI01还顺利达成海外授权，交易金额超5亿美元。END👇关注药渡数据媒体矩阵

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