A Phase 2, Open-label, Multicenter Study to Evaluate the Safety and Efficacy of Belumosudil in Black or African American, American Indian or Alaska Native, and Native Hawaiian or Other Pacific Islander Participants With Chronic Graft Versus Host Disease (cGVHD) After At Least 2 Prior Lines of Systemic Therapy

The purpose of this study is to measure safety and efficacy of oral belumosudil in Black or African American, American Indian or Alaska Native, and Native Hawaiian or Other Pacific Islander male and female participants with cGVHD who have previously been treated with at least 2 prior lines of systemic therapy aged 12 years and above.
The duration of participants participation will be up to 4 weeks for screening, treatment until clinically significant progression of disease, and 4 weeks of safety follow-up, and then long-term follow-up every 12 weeks.1 Cycle = 28 days.

开始日期2025-06-16

申办/合作机构

Kadmon Holdings, Inc.

NCT06751602

/ Not yet recruiting临床2期IIT

A Phase 2, Randomized, Placebo-Controlled Study to Evaluate Belumosudil for the Abrogation of Interstitial Fibrosis and Tubular Atrophy in De Novo Kidney Transplant Recipients

This is a randomized, double-blind, placebo-controlled trial in de novo kidney transplant patients to determine if the addition of belumosudil (brand name- REZUROCK®) on the background of standard immunosuppression will prevent fibrosis in the kidney transplant. Interstitial expansion is the precursor of interstitial fibrosis and graft loss. The hypothesis underlying the study is that abgrogating the fibrogenic effects of the RhoA pathway with belumosudil will reduce structural damage in transplanted kidneys and possible subsequent transplant failure.

开始日期2025-04-15

申办/合作机构

The Methodist Hospital Research Institute

NCT06476132

/ Recruiting临床2期IIT

Belumosudil to Block Chronic Lung Allograft Dysfunction (CLAD) in High Risk Lung Transplant Recipients: A Randomized, Multicenter, Double Blind, Placebo-Controlled Trial (CTOT-47)

The purpose of this study is to see if taking the study drug, Belumosudil, for 52 weeks in addition to your usual care and medication, will prevent Chronic Lung Allograft Dysfunction (CLAD) in participants who have a lung biopsy that shows evidence of rejection or inflammation to the transplanted lung(s). For this study, biopsies that show evidence of Acute Rejection (AR), Lymphocytic Bronchiolitis (LB), Organizing Pneumonia (OP) or Acute Lung Injury (ALI) are referred to as "Qualifying Biopsies"; patients who had evidence of one or more of these conditions on a recent biopsy are eligible for enrollment in this study. Belumosudil is an investigational drug that blocks a molecule in the body that reduces inflammation and scarring and may play a role in the development and progression of CLAD. Belumosudil is a drug approved by the FDA to treat adults and children 12 years and older with chronic graft-versus-host disease (cGVHD), a condition with some similarities to CLAD.
The primary objective it to determine the efficacy of treatment with Belumosudil + maintenance immunosuppression (IS) versus placebo + maintenance IS on preventing the subsequent development of probable or definite CLAD, lung retransplant, or death.

开始日期2025-03-12

申办/合作机构

National Institute of Allergy & Infectious Diseases

100 项与 ROCK2 x ROCK1 相关的临床结果

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100 项与 ROCK2 x ROCK1 相关的转化医学

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0 项与 ROCK2 x ROCK1 相关的专利（医药）

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项与 ROCK2 x ROCK1 相关的文献（医药）

2025-06-01·Tissue and Cell

Polygala crotalarioides attenuates erectile dysfunction through improving Rho/ROCK signaling pathway mediated thyroid and gonadal function in kidney Yang deficiency ED rat

Article

作者: Chen, Xizhi ; Wen, Weibo ; Chen, Yao

This study aimed to explore effectiveness and related mechanisms of Polygala crotalarioides in treating erectile dysfunction (ED). Hydrocortisone was used to establish a kidney-Yang deficiency ED rat model. Levels of triiodothyronine(T3), thyroxine(T4), testosterone(T), estradiol(E2) and expressions of RhoA, ROCK1, ROCK2 were determined. Immunofluorescence staining was used to detect CD34 in penile tissues. Compared with normal rats, T3, T4, T, E2 levels in serum of ED rat model were significantly reduced (P < 0.05), while RhoA, ROCK1, ROCK2 expressions were significantly higher (P < 0.05). High- and medium-dose of Polygala crotalarioides significantly attenuated erectile dysfunction, but low-doses of Polygala crotalarioides were ineffective. High and medium dose of Polygala crotalarioides and sildenafil significantly increased weight of ED rats compared to Model group (P < 0.05). T3, T4, E2, and T levels in low-dose, medium-dose, and high-dose of Polygala crotalarioides group were increased compared to Model group (P < 0.05). Compared with Model group, RhoA, ROCK1, and ROCK2 expressions in penile tissue of rats in low-, medium-, high-dose of Polygala crotalarioides group were reduced (P < 0.05). High-, medium-, and low-dose Polygala crotalarioides significantly increased CD34 compared with ED rat (P < 0.05). In conclusion, Polygala crotalarioides attenuated erectile dysfunction and improved thyroid and gonadal function by regulating Rho/ROCK pathway in kidney Yang-deficiency ED rat.

2025-02-21·ACS Chemical Biology

Discovery of Dual ROCK1/2 Inhibitors from Nocardiopsis sp. under Metal Stress

Article

作者: Kang, Suk Woo ; Kim, Hasun ; Jung, Sang Hoon ; Song, Dae-geun ; Bui, Thinh T. M. ; Jeong, Hyeongju ; Moon, Kyuho ; Ko, Hyejin ; Um, Soohyun

Rho-associated protein kinase (ROCK) inhibitors are promising therapeutic agents for reducing elevated intraocular pressure in patients with glaucoma. We explored new ROCK inhibitors derived from bioactive metabolites produced by microbes, specifically cryptic metabolites from Nocardiopsis sp. MCY7, using a liquid chromatography-mass spectrometry-based chemical analysis approach integrated with metal stress-driven isolation. This strategy led to the identification of two previously undescribed linear peptides, nocarnickelamides A and B (1 and 2), and an unreported cittilin derivative, cittilin C (3). The planar structures of 1-3 were elucidated using UV spectroscopy, high-resolution mass spectrometry, and nuclear magnetic resonance. The absolute configurations of 1 and 2 were assigned using the advanced Marfey's method. Biological assays demonstrated that nocarnickelamides (1 and 2) exhibited dual inhibitory activity against ROCK1 (IC₅₀ 29.8 and 14.9 μM, respectively) and ROCK2 (IC₅₀ 27.0 and 21.9 μM, respectively), with molecular simulations suggesting binding to the ATP-binding site. In human trabecular meshwork cells, 2 significantly inhibited the activation of ROCK-regulated cytoskeletal contraction markers such as the myosin light chain. Nocarnickelamide B (2) is a novel dual ROCK1/2 inhibitor and a potential pharmacophore for designing new therapeutic agents to reduce intraocular pressure in glaucoma.

2025-02-16·Future Medicinal Chemistry

Pioneering first-in-class HDAC-ROCK inhibitors as potential multitarget anticancer agents

Article

作者: Beljkas, Milan ; Oljacic, Slavica ; Djuric, Ana ; Jallet, Corinne ; Nikolic, Katarina ; Vuletic, Ana ; Ruzic, Dusan ; Petkovic, Milos ; Cadet-Daniel, Véronique ; Santibanez, Juan F. ; Arimondo, Paola B. ; Srdic-Rajic, Tatjana ; Tchiehe, Guilaine Nchugoua

AIMWith the aim of simultaneously modulating the epigenetic system and the protein kinase pathway, we selected the enzyme histone deacetylase (HDAC) and the Rho-associated protein kinases (ROCK) as desired targets to develop potential multitarget anticancer agents with additional antimetastatic properties. We report here the rational design, synthesis, and biological evaluation of the first-in-class HDAC/ROCK multitarget inhibitors in pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC).MATERIALS AND METHODSA molecular docking study performed with the Gold software was used to develop HDAC/ROCK multitarget inhibitors. IC₅₀ values were determined by enzyme assays. The cytotoxicity, anti-migratory and anti-invasive properties of the inhibitors were evaluated using triple-negative breast cancer cells (MDA-MB-231 and HCC 1973) and pancreatic ductal adenocarcinoma cells (Panc-1 and MiaPaCa-2).RESULTSC-9 showed significant inhibition of HDAC6, ROCK1 and ROCK2. At the same time, this compound showed strong antiproliferative effects on MDA-MB-231, MiaPaCa-2 and Panc-1 cell lines with IC₅₀ values of 5.81 μM, 3.87 μM and 19.57 μM. In addition, it demonstrated great anti-invasive and anti-migratory effects.CONCLUSIONThe findings of this study strongly suggest that the simultaneous inhibition of ROCK and HDACs holds significant potential as a promising therapeutic strategy in the advancement of cancer treatment.

项与 ROCK2 x ROCK1 相关的新闻（医药）

2025-04-28

·ioncology

贝舒地尔领航cGVHD二线靶向治疗，实现cGVHD控制与GVL效应保留的双赢，为移植患者带来双重守护

点击蓝字关注我们造血干细胞移植（HSCT）为血液病患者带来了治愈的希望，但移植后复发及慢性移植物抗宿主病（cGVHD）依然是临床面临的主要难题。传统上，cGVHD的治疗主要依赖免疫抑制剂，虽可缓解症状，但常导致复发风险上升1。贝舒地尔作为全球首个高选择性ROCK2抑制剂，其快速起效、持久缓解和良好安全性，使其成为cGVHD治疗中的核心选择，贝舒地尔凭借其独特的作用机制，能够有效控制cGVHD的进展，同时保留移植物抗白血病（GVL）效应，实现对免疫系统的双向精准调节。这一双重作用不仅突破了传统免疫抑制治疗的局限，为移植后患者带来了更优的治疗选择，也显著提升了长期生存和康复的可能性2。2025年4月18日，《CSCO造血干细胞移植治疗血液系统疾病指南》重磅更新，明确将贝舒地尔确立为cGVHD二线靶向治疗的领航药物3。本文将基于供者免疫细胞介导的GVL与GVHD的双重效应，阐明贝舒地尔治疗移植后cGVHD的双重靶向作用，以飨读者。贝舒地尔获2025 CSCO指南Ⅰ级推荐，领航二线治疗新格局2025《CSCO造血干细胞移植治疗血液系统疾病指南》基于循证医学证据、兼顾诊疗产品的可及性、吸收精准医学新进展，把cGVHD二线药物分为Ⅰ级推荐、Ⅱ级推荐和Ⅲ级推荐，明确而具体，为临床治疗提供了依据和指导。针对cGVHD的二线治疗，指南进一步明确了贝舒地尔的核心地位（Ⅰ级推荐，2A类证据）(表1）3。贝舒地尔获得指南的高度认可，与其兼顾抗炎和抗纤维化的双重作用机制，卓越的疗效和良好的安全性密切相关。表1. cGVHD二线治疗的Ⅰ级推荐药物复发与cGVHD：移植患者康复路上的双重挑战HSCT是目前治疗血液系统疾病最有效的方法之一，但也面临诸多挑战，恶性肿瘤复发风险和cGVHD的发生风险给临床管理增加了难度，也是死亡的主要原因4。既往研究结果显示移植患者复发后的中位总生存（OS）仅4-6个月，cGVHD相关非复发死亡率（NRM）呈逐年上升趋势，预计12年NRM可高达40%5,6。供者T细胞等免疫细胞，能够消除残留的白血病细胞，这种免疫介导的应答称为GVL效应，可以防止原发性恶性肿瘤的复发7。然而，供者的同种异体免疫反应针对健康组织可引发cGVHD，是移植后主要并发症之一8。GVL与GVHD由供者免疫细胞介导，常同时发生（图1）。目前cGVHD的一线治疗仍以糖皮质激素（CS）联合或不联合钙调磷酸酶抑制剂（CNI）等免疫抑制治疗为主，但—线治疗的有效率仅为50%，既往研究表明70.9%的患者最终需要接受二线治疗1,9。不仅如此，免疫抑制剂在治疗的同时还会削弱GVL效应，增加疾病复发风险1。这种治疗困境促使临床急需既能有效控制cGVHD，又能保留GVL效应的新型治疗方案。图1. 供者T细胞和GVL及GVHD7,8重塑免疫稳态：控制GVHD与保留GVL效应的双赢策略免疫逃逸是白血病复发和GVL效应失效的关键，因疾病复发过程中，T细胞功能受抑，白血病细胞得以逃避免疫攻击10。免疫失衡则是cGVHD发生的重要原因，Treg细胞对Th17细胞具有调控作用。当缺乏Treg细胞对Th17细胞的抑制时，可导致Th17细胞过度活化，Treg细胞数量的减少或功能缺陷是cGVHD发病的重要原因11。免疫稳态对于控制GVHD同时保留GVL效应起重要作用，Treg细胞在调节适应性免疫和维持免疫耐受方面发挥着重要作用，在预防GVHD同时保留GVL效应中的机制12。既往证据显示，预防性输注Treg可将急性GVHD风险降低30%-50%，同时Treg选择性抑制病理免疫反应，不影响供体T细胞对白血病细胞的杀伤作用，因此移植术后及时使用可有效降低复发率，从而改善异基因HSCT（allo-HSCT）的治疗效果（图2）13-14。图2. 控制T细胞增殖可有效将GVL效应从GVHD中分离15双管齐下：贝舒地尔重建免疫耐受，恢复免疫平衡贝舒地尔作为高选择性ROCK2抑制剂，通过独特机制实现了治疗突破。其对ROCK2的选择性是ROCK1的100倍，显著下调Th17细胞和Tfh细胞及其相关的促炎细胞因子 (IL-17、IL-21），提高Treg细胞的功能和数量，有效维持抑制促炎免疫细胞的功能，从而不影响GVL启动。这种精准靶向特性使贝舒地尔兼具抗炎和抗纤维化作用，能够重塑免疫稳态，以持续为HSCT保驾护航16-20。基础研究证实，贝舒地尔治疗能够显著降低小鼠的cGVHD评分。同时，在植入效应T细胞的小鼠中，贝舒地尔组与对照组的肿瘤细胞负荷下降曲线几乎一致，说明贝舒地尔在缓解cGVHD的同时，并不削弱T细胞对肿瘤细胞的杀伤能力（图3）21。图3. 贝舒地尔治疗cGVHD的同时可以保留GVL效应健康护航：贝舒地尔实现控制cGVHD，降低疾病复发双目标随机、开放标签、国际多中心关键性II期研究ROCKstar20 ，共纳入132例接受过2-5线系统性治疗后出现持续活动性cGVHD表现的患者，98%为中重度，伴有多器官受累和纤维化表现，中位随访14个月。贝舒地尔中国II期研究（n=20）22的重度患者占比高达66.7%，中位随访12.9个月。两项研究均证实，贝舒地尔改善缓解和生存，可减少免疫抑制剂使用，可进一步助益GVL效应的保留（图4、5）。图4. 贝舒地尔治疗cGVHD高缓解高生存，低复发图5. 贝舒地尔治疗科室CS和CNI减量，助力保留GVL效应总结面对造血干细胞移植后疾病复发和cGVHD两大挑战，恢复免疫稳态对控制GVHD同时保留GVL效应至关重要，通过下调Th17细胞/抑制促炎因子、上调Treg细胞的数量及功能，可实现GVL效应与GVHD的分离，提高患者预后。贝舒地尔有效恢复免疫平衡，兼顾cGVHD的改善和GVL效应的保留, 不增加复发风险，持续为移植患者保驾护航。参考文献：（上下滑动查看更多）1.中华医学会血液学分会干细胞应用学组. 中华血液学杂志,2024,45(08)：713-726.2. Jagasia M,et al. J Clin Oncol. 2021 Jun 10;39(17):1888-1898..3.中国临床肿瘤学会(CSCO). 造血干细胞移植治疗血液系统疾病指南(2025版)4.Søborg A, et al. Eur J Haematol. 2024 May;112(5):802-809.5.Shi W, et al. Acta Pharm Sin B. 2020 Nov;10(11):2125-2139.6.Zachariah DeFilipp et al. Blood Adv (2021) 5 (20): 4278–42847.Sweeney C, Vyas P. Front Oncol. 2019 Nov 19;9:12178. Fiuza-Luces C, et,al. Bone Marrow Transplant. 2016;51(1):13-269.Bachier CR, et al. Transplant Cell Ther. 2021;27(6):504.e1-504.e6.10. Yan Y, et al. Exp Hematol. 2022 May;109:1-10.e1.11. Advances and Controversies in Hematopoietic Transplantation and Cell Therapy Series Editors：Syed A. Abutalib Deerfield, Illinois, USA and James O. Armitage Omaha, Nebraska, USA12. Di Ianni M, et al. Cells. 2024 Jan 11;13(2):134.13. Pacini CP, et al. Front Immunol. 2024 Apr 22;15:1339318.14. Brunstein CG, et al. Blood. 2011 Jan 20;117(3):1061-70.15. Heinrichs J, et al. J Immunol Res Ther. 2016;1(1):1-14.16.Zanin-Zhorov A, et al. Proc Natl Acad Sci USA. 2014;111(47):16814-16819. .17.Flynn R, et al. Blood. 2016;127(17):2144-2154.18.Weiss JM, et al. Sci Signal. 2016;9(437):ra73.19. Clin Immunol. 2021 Sep:230:108823.20. Corey Cutler, et al. Blood. 2021 Dec 2;138(22):2278-2289.21.Flynn R, et al. Blood. 2016;127(17):2144-2154.22. Wang Y, et al. BMC Med. 2024;22(1):142.免责声明：该信息仅作医学和科研参考，赛诺菲不建议以任何与您所在国家所批准的处方信息不符的方式使用本产品。本材料仅供医疗卫生专业人士使用。MAT-CN-2508014；V1.0；批准日期：2025年4月（来源：《血液时讯》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

CSCO会议免疫疗法

2025-01-15

·Pharma CMC

正大天晴「罗伐昔替尼」在美获批临床

今日（1月15日），正大天晴宣布，其自主研发的具有全新化学结构的JAK/ROCK抑制剂罗伐昔替尼片（TQ05105）II期临床试验申请（IND）获得FDA批准，拟用于治疗慢性移植物抗宿主病（cGVHD）。2024年7月，TQ05105已在国内提交上市申请，用于治疗中高危骨髓纤维化（MF）。 TQ05105是一类新型、口服的JAK/ROCK抑制剂。体外试验结果显示，TQ05105能够抑制JAK家族激酶活性及ROCK激酶活性，抑制细胞中STAT3和STAT5的磷酸化水平，从而抑制JAK/STAT信号通路传导作用，发挥抗肿瘤活性，同时抑制ROCK2，重建免疫平衡。在2024年欧洲肿瘤内科学年会（ESMO）上，正大天晴公布了TQ05105对比羟基脲治疗中高危骨髓纤维化（MF）患者的关键II期临床研究数据[5]。结果表明，TQ05105对比对照组，第24周脾脏体积较基线缩小超过35%的患者比例分别为：58.33% vs 22.86%；TQ05105试验组体质症状最佳改善率为61.11%。患者中毒性可耐受，没有出现新的安全性信号。此外，正大天晴还在加速推进TQ05105的多项联合研究，以充分挖掘其临床价值，如联合BET抑制剂或BCL-2抑制剂用于治疗中高危骨髓纤维化（MF）的临床研究，已取得较为积极的初步结果。

临床申请临床2期

2025-01-07

·生物制药小编

两任CEO跑路后，核心管线终暴雷

对于Valo的CEO来说，公布OPL-0401的临床数据似乎是个烫手山芋，因为在2024年的半年多时间内，Valo接连两位CEO离任。近日，Valo Health公布了其OPL-0401在糖尿病视网膜病变患者中的Ⅱ期 SPECTRA临床的顶线数据，结果显示，该项临床试验未达到其主要或次要终点，Valo已经暂停开发。走了两任CEO OPL-0401是一种口服非选择性ROCK（Rho激酶）1和2抑制剂，用于治疗非增殖性糖尿病视网膜病变，2021年公司从赛诺菲获得授权引进。在这项Ⅱ期SPECTRA临床公布前的时间内，公司连续跑了两任CEO。早在2024年1月，Valo宣布自公司成立便担任CEO职位的David Berry即将离任，同时，任命公司副总裁兼首席财务官的Graeme Bell为临时CEO。但是这位临时CEO上任半年后，在OPL-0401关键Ⅱ期临床数据发布前的关键时期也离职了。虽然没有直接证据表明两任CEO的离开是因为OPL-0401的原因，但是也让外界对其即将公布的临床数据产生了担忧—会不会是因为OPL-0401的临床表现不佳？” 临床结果不出大家的意料，SPECTRA临床宣告失败，在主要终点—DR严重程度评分上，OPL-0401相比安慰剂未能实现统计学上的显著改善，基于此，公司决定暂停对OPL-0401的开发，并计划寻找外部合作伙伴。宣布OPL-0401临床失败的消息留给了新上任不久的CEO Brian Alexander，是Flagship的合伙人，曾经是Foundation Medicine的CEO—Foundation Medicine于2015年被罗氏收购。从这位CEO的发言来看，也是主要为了稳住大家的信心。在新闻公告中， Brian Alexander强调了OPL-0401并非公司自研，OPL-0401的临床失败并不代表公司平台的失败，也不会影响公司未来的发展方向。公司未来将把重点放在Opal平台上，继续发现新靶点。还有啥管线? Valo Health成立于2019年，是一家AI制药公司，由知名风投公司Flagship Pioneering孵化。 Valo的核心技术平台为Opal ，该平台能够将真实世界的患者数据与人体组织建模和机器学习模型相结合，加快新分子的发现过程。 OPL-0401本身就是公司最领先的管线。虽然CEO口头上说不会影响公司未来的发展，但是该公司于去年还放弃了一条临床阶段管线OPL-0301的开发计划，OPL-030也推进到了临床Ⅱ期阶段，被开发用于心肌梗死。 OPL-0401本身就是公司最领先的管线，如今也被放弃，现在Valo已经没有任何一款进入临床的管线了。 Valo的最新一轮融资还是2021年的B轮，之后并未再披露新的融资，并且尝试通过与Khosla Ventures的SPAC合并上市也失败了。好在2023年与诺和诺德达成了合作，收到了6000万美元预付款。不过，就现阶段而言，Valo仍需要尽快推进临床来验证公司平台技术的价值，来稳住市场的信心。总结近年来，AI制药发展迅速，成为资本市场的新宠，但是AI设计的药物在进入临床后也面临着理想与现实之间的巨大差距，大多数未能挺过Ⅱ期阶段。今年以来，也有不少像Recursion、Bioage Labs等AI制药公司经历了核心管线的失败。相比传统新药开发，AI是否显著提高了药物的临床成功率目前还是一个无解的问题。参考出处：火热的AI制药，悄悄停止了一些临床 https://www.valohealth.com/press/valo-health-announces-topline-results-from-phase-2-spectra-study-of-opl-0401-in-patients-with-diabetic-retinopathy

临床2期并购高管变更