更新于：2024-05-01

ROCK2

Rho相关蛋白激酶-2

更新于：2024-05-01

基本信息

别名

KIAA0619、p164 ROCK-2、Rho associated coiled-coil containing protein kinase 2

+ [6]

简介

Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus. Plays an important role in generating the circadian rhythm of the aortic myofilament Ca(2+) sensitivity and vascular contractility by modulating the myosin light chain phosphorylation.

关联

项与 ROCK2 相关的药物

Belumosudil

贝舒地尔

靶点

ROCK1 x ROCK2

作用机制

ROCK1抑制剂 [+1]

在研机构

Sanofi [+8]

原研机构

Kadmon Pharmaceuticals LLC

在研适应症

慢性移植物抗宿主病 [+3]

非在研适应症

自身免疫性疾病 [+5]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2021-07-16

Sovesudil

靶点

ROCK1 x ROCK2

作用机制

ROCK1抑制剂 [+1]

在研机构

pH Pharma Co., Ltd.初创企业

原研机构

Amakem NV

在研适应症

开角型青光眼

非在研适应症-

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期1800-01-20

OPL-0401

靶点

ROCK1 x ROCK2

作用机制

ROCK1抑制剂 [+1]

在研机构

Valo Health LLC初创企业

原研机构

Courier Therapeutics, Inc.初创企业

在研适应症

非增殖性糖尿病视网膜病变 [+1]

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 ROCK2 相关的临床试验

NCT05567406 / Recruiting临床2期

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2024-05-02

申办/合作机构

Kadmon Holdings, Inc.

NCT06300320 / Not yet recruiting临床2期

A Randomized, Open-label, Multicenter Phase II Clinical Trial of Rovadicitinib in the Treatment of Third-line and Subsequent Moderate to Severe Chronic Graft-versus-host Disease (cGVHD).

This is an open, multi-center clinical study designed to evaluate the efficacy and safety of TQ05105 Tablets in patients with chronic graft-versus-host disease

开始日期2024-04-01

申办/合作机构

正大天晴药业集团股份有限公司

ChiCTR2400082056 / Suspended早期临床1期IIT

An exploratory clinical trial to evaluate the safety and efficacy of TDI01 suspension in the patients with hepatic fibrosis

开始日期2024-03-20

申办/合作机构-

100 项与 ROCK2 相关的临床结果

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100 项与 ROCK2 相关的转化医学

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0 项与 ROCK2 相关的专利（医药）

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1,527

项与 ROCK2 相关的文献（医药）

2024-02-20·Animal models and experimental medicine

"Baihui" (DU20)-penetrating "Qubin" (GB7) acupuncture on blood-brain barrier integrity in rat intracerebral hemorrhage models via the RhoA/ROCK II/MLC 2 signaling pathway.

Article

作者: Ce Zhang ; Jia Zheng ; Xueping Yu ; Binglin Kuang ; Xiaohong Dai ; Lei Zheng ; Weiwei Yu ; Wei Teng ; Hongtao Cao ; Mingyue Li ; Jiayong Yao ; Xiaoying Liu ; Wei Zou

BACKGROUND:

Blocking the RhoA/ROCK II/MLC 2 (Ras homolog gene family member A/Rho kinase II/myosin light chain 2) signaling pathway can initiate neuroprotective mechanisms against neurological diseases such as stroke, cerebral ischemia, and subarachnoid hemorrhage. Nevertheless, it is not clear whether and how disrupting the RhoA/ROCK II/MLC 2 signaling pathway changes the pathogenic processes of the blood-brain barrier (BBB) after intracerebral hemorrhage (ICH). The present investigation included the injection of rat caudal vein blood into the basal ganglia area to replicate the pathophysiological conditions caused by ICH.

METHODS:

Scalp acupuncture (SA) therapy was performed on rats with ICH at the acupuncture point "Baihui"-penetrating "Qubin," and the ROCK selective inhibitor fasudil was used as a positive control to evaluate the inhibitory effect of acupuncture on the RhoA/ROCK II/MLC 2 signaling pathway. Post-assessments included neurological deficits, brain edema, Evans blue extravasation, Western blot, quantitative polymerase chain reaction, and transmission electron microscope imaging.

RESULTS:

We found that ROCK II acts as a promoter of the RhoA/ROCK II/MLC 2 signaling pathway, and its expression increased at 6 h after ICH, peaked at 3 days, and then decreased at 7 days after ICH, but was still higher than the pre-intervention level. According to some experimental results, although 3 days is the peak, 7 days is the best time point for acupuncture treatment. Starting from 6 h after ICH, the neurovascular structure and endothelial cell morphology around the hematoma began to change. Based on the changes in the promoter ROCK II, a 7-day time point was selected as the breakthrough point for treating ICH model rats in the main experiment. The results of this experiment showed that both SA at "Baihui"-penetrating "Qubin" and treatment with fasudil could improve the expression of endothelial-related proteins by inhibiting the RhoA/ROCK II/MLC 2 signaling pathway and reduce neurological dysfunction, brain edema, and BBB permeability in rats.

CONCLUSION:

This study found that these experimental data indicated that SA at "Baihui"-penetrating "Qubin" could preserve BBB integrity and neurological function recovery after ICH by inhibiting RhoA/ROCK II/MLC 2 signaling pathway activation and by regulating endothelial cell-related proteins.

2024-02-07·Aging

Mechanism of Erianin anti-triple negative breast cancer based on transcriptomics methods and network pharmacology.

Article

作者: Ming Li ; Yuan Zhao ; Huimin Li ; Shiyao Kang ; Xuming Deng ; Miaomiao Sheng

Triple negative breast cancer (TNBC) is a highly aggressive illness that lacks effective targeted treatments. Although Erianin has shown potential antitumor properties, its precise mechanism of action and target in TNBC remain unclear, hampering the development of drugs. The present study investigated the underlying mechanism of action of Erianin in treating TNBC by using transcriptomics and network pharmacology approaches. We evaluated Erianin's bioactivity in TNBC cell lines and xenograft tumor models. The results showed that Erianin significantly inhibited TNBC cell proliferation and impeded tumor growth. A subsequent analysis of transcriptomic and network pharmacological data identified 51 mutual targets. Analysis of protein-protein interactions identified eight hub targets. Furthermore, molecular docking indicated that the PPARA binding energy was the lowest for Erianin among the hub targets, followed by ROCK2, PDGFRB, CCND1, MUC1, and CDK1. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis showed that the common targets were associated with multiple cancer-related signaling pathways, including focal adhesion, PI3K-Akt signaling pathway, Rap1 signaling pathway, microRNAs in cancer, and human papillomavirus infection. The results of the Western blot and immunohistochemistry experiment further showed that Erianin could suppress PI3K/Akt signaling pathway activation. After co-incubation with SC79, the cell inhibition rate of Erianin was decreased, which further confirmed that Erianin inhibits TNBC progression via the PI3K-AKT signaling pathway. In conclusion, our results indicated that Erianin has the potential to inhibit the proliferation of TNBC by downregulating the PI3K/AKT signaling pathway by transcriptomics and network pharmacology. Therefore, Erianin appears to be a promising compound for the effective treatment of TNBC.

2024-02-01·Physical therapy

Constraint-Induced Movement Therapy Promotes Myelin Remodeling and Motor Function by Mediating Sox2/Fyn Signals in Rats with Hemiplegic Cerebral Palsy.

Article

作者: Chaoqiong Fu ; Hongmei Tang ; Liru Liu ; Yuan Huang ; Hongyu Zhou ; Shiya Huang ; Tingting Peng ; Peishan Zeng ; Xubo Yang ; Lu He ; Kaishou Xu

OBJECTIVE:

Hypoxic-ischemic brain injury in infants often leads to hemiplegic motor dysfunction. The mechanism of their motor dysfunction has been attributed to deficiencies of the transcription factor SRY (sex-determining region) box 2 (Sox2) or the non-receptor-type tyrosine kinase Fyn (involved in neuronal signal transduction), which causes a defect in myelin formation. Constraint-induced movement therapy (CIMT) following cerebral hypoxia-ischemia may stimulate myelin growth by regulating Sox2/Fyn, Ras homolog protein family A (RhoA), and Rho-associated kinase 2 (ROCK2) expression levels. This study investigated how Sox2/Fyn regulates myelin remodeling following CIMT to improve motor function in rats with hemiplegic cerebral palsy (HCP).

METHODS:

To investigate the mechanism of Sox2 involvement in myelin growth and neural function in rats with HCP, Lentivirus-Sox2 adeno-associated virus and negative control-Lenti-Sox2 adeno-associated virus were injected into the lateral ventricle. The rats were divided into a control group and an HCP group with different interventions (CIMT, Lenti-Sox2 [LS], or negative control-Lenti-Sox2 [NS] treatment), yielding the HCP, HCP plus CIMT (HCP + CIMT), HCP + LS, HCP + LS + CIMT, HCP + NS, and HCP + NS + CIMT groups. Front-limb suspension and RotaRod tests, Golgi-Cox staining, transmission electron microscopy, immunofluorescence staining, Western blotting, and quantitative polymerase chain reaction experiments were used to analyze motor function, dendrite/axon area, myelin ultrastructure, and the levels of expression of oligodendrocytes and Sox2/Fyn/RhoA/ROCK2 in the motor cortex.

RESULTS:

The rats in the HCP + LS + CIMT group had better values for motor function, dendrite/axon area, myelin ultrastructure, oligodendrocytes, and Sox2/Fyn/RhoA/ROCK2 expression in the motor cortex than rats in the HCP and HCP + NS groups. The improvement of motor function and myelin remodeling, the expression of oligodendrocytes, and the expression of Sox2/Fyn/RhoA/ROCK2 in the HCP + LS group were similar to those in the HCP + CIMT group.

CONCLUSION:

CIMT might overcome RhoA/ROCK2 signaling by upregulating the transcription of Sox2 to Fyn in the brain to induce maturation and differentiation of oligodendrocytes, thereby promoting myelin remodeling and improving motor function in rats with HCP.Impact. The pathway mediated by Sox2/Fyn could be a promising therapeutic target for HCP.

104

项与 ROCK2 相关的新闻（医药）

2024-04-04

·BioSpace

Ovid Therapeutics to Present at the 23rd Annual Needham Virtual Healthcare Conference

NEW YORK, April 04, 2024 (GLOBE NEWSWIRE) -- Ovid Therapeutics Inc. (NASDAQ: OVID), a biopharmaceutical company dedicated to meaningfully improving the lives of people affected by rare epilepsies and brain conditions, today announced that management will participate in a virtual presentation at the 23rd Annual Needham Virtual Healthcare Conference on Thursday, April 11, 2024, at 9:30 a.m. ET. A live webcast of the Needham presentation can be accessed through the Events & Presentations section of the Company’s website at investors.ovidrx.com. An archived replay of the webcast will be available on the Company’s website following the live presentation for approximately 90 days. About Ovid Therapeutics Ovid Therapeutics Inc. is a New York-based biopharmaceutical company that is dedicated to meaningfully improving the lives of people affected by certain epilepsies and brain conditions with seizure symptoms. The Company is advancing a pipeline of novel, targeted small molecule candidates that modulate the intrinsic and extrinsic factors involved in neuronal hyperexcitability causative of seizures and other neurological symptoms. Ovid is developing: OV888 (GV101), a potent and highly selective ROCK2 inhibitor, for the potential treatment of lesions associated with cerebral cavernous malformations and other brain disorders; OV329, a GABA-aminotransferase inhibitor, a potential therapy for treatment-resistant seizures; and OV350, a direct activator of the KCC2 transporter, for the potential treatment of epilepsies and other psychiatric conditions. Ovid also maintains a significant financial interest in the future regulatory development and potential commercialization of soticlestat, which Takeda is responsible for advancing globally. Soticlestat is a cholesterol 24-hydroxylase inhibitor, which is currently in Phase 3 trials for Dravet and Lennox-Gastaut syndromes. For more information about these and other Ovid research programs, please visit . Forward-Looking Statements This press release includes certain disclosures by Ovid that contain “forward-looking statements,” including, without limitation: statements regarding the potential use and development of OV888 (GV101), OV329, OV350 and compounds from Ovid's library of direct activators of KCC2; the potential therapeutic opportunity of OV888 (GV101), OV329 and compounds from Ovid's library of direct activators of KCC2; the potential opportunity for soticlestat; the timing and data readout of Takeda’s two pivotal Phase 3 trials evaluating soticlestat for Dravet syndrome and Lennox-Gastaut syndrome; Ovid’s expectations regarding the duration of its cash runway and the expectation that it will support the advancement of Ovid’s pipeline and Ovid's potential future business development opportunities. You can identify forward-looking statements because they contain words such as “anticipates,” “expected,” “intends,” “may,” “potentially,” “seek,” and “will,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances). Forward-looking statements are based on Ovid’s current expectations and assumptions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that may differ materially from those contemplated by the forward-looking statements, which are neither statements of historical fact nor guarantees or assurances of future performance. Important factors that could cause actual results to differ materially from those in the forward-looking statements include, without limitation, uncertainties inherent in the preclinical and clinical development and regulatory approval processes, risks related to Ovid’s ability to achieve its financial objectives, the risk that Ovid may not be able to realize the intended benefits of its technology or its business strategy, or risks related to Ovid’s ability to identify business development targets or strategic partners, to enter into strategic transactions on favorable terms, or to consummate and realize the benefits of any business development transactions. Additional risks that could cause actual results to differ materially from those in the forward-looking statements are set forth under the caption “Risk Factors” in Ovid’s Annual Report on Form 10-K filed with the Securities and Exchange Commission (“SEC”) on March 8, 2024 and in future filings Ovid makes with the SEC. Any forward-looking statements contained in this press release speak only as of the date hereof, and Ovid assumes no obligation to update any forward-looking statements contained herein, whether because of any new information, future events, changed circumstances or otherwise, except as otherwise required by law. Contacts Investor Relations: Garret Bonney 617-735-6093 IR@ovidrx.com

临床3期

2024-03-15

·创鉴汇

成立不到2年！14家“硬核”创新药新锐获融资

▎药明康德内容团队编辑2024年，“创新药”一词首次进入政府工作报告，众多行业媒体纷纷解读，推测这一产业对于国家发展战略的重要性进一步提升。作为创新药领域的重要生力军，初创公司对于推动产业科学技术创新、满足未竟医疗需求具有显著意义。本文以全球为视角，盘点2024年该领域初创公司的融资动态，供读者参阅。据不完全统计，2024年至今，14家成立不到2年的创新药公司获得了新一轮融资。其中包括：集合6家公司管线及技术的皮肤科新锐，诺奖得主创办的ADC+蛋白降解新秀，完成2024年biotech合并第一案的先天免疫学公司等。其他值得关注的亮点如下：多家新锐首轮融资金额可观：根据公开资料，作为成立以来的第一轮融资，Alys Pharmaceuticals、Firefly Bio、Calluna Pharma，以及Amlogenyx，均实现了5000万美元及以上的大额融资，对于初创biotech来说，已是不俗的金额，侧面认可了其发展潜力。学术创业吸引资源流入：获融资公司中，Alys Pharmaceuticals及Firefly Bio由诺贝尔奖得主联合创办，均获得了1亿美元左右的早期融资支持。位于中国广东的奥礼生物，创始团队来自伦敦大学学院，成立以来已完成2轮千万元级融资。免疫系统疾病为重点关注疾病领域：5家公司布局了免疫系统疾病领域的药物研发项目，包括聚焦干细胞疗法的ImmunoFree，关注双特异性抗体与ADC药物的Attovia，主打ROCK2抑制剂开发的Graviton等。集6家公司之大成！诺奖得主联合创办皮肤科新锐获1亿美元融资2月13日，投资公司Medicxi将六家专注于皮肤适应症的生物科技公司结合，推出具有多种平台技术与研发管线的Alys Pharmaceuticals，并同时以1亿美元种子融资支持其于免疫皮肤疾病领域当中创新疗法的开发。这笔资金将帮助Alys实现到2026年底前完成7至10项概念验证（POC）以及至少一个项目进入临床注册研究的目标。Alys由Medicxi和几位知名的皮肤病学和科学专家（包括诺贝尔奖得主Craig Mello博士）共同创立，致力于重新定义皮肤病治疗的前景。该公司结合了6家公司的管线和平台，其中包括开发皮肤疾病siRNA疗法的Aldena Therapeutics，预防放射疗法对健康皮肤的副作用的Graegis Pharmaceuticals等。目前，Alys共拥有十多个活跃项目，凭借其尖端平台，其管线将可能进一步增长，并涵盖包含炎症性疾病、自身免疫性疾病、癌症患者和罕见皮肤病等适应症。ADC+蛋白降解！诺奖得主联合创建新锐融资近亿美元2月16日，诺贝尔化学奖得主Carolyn Bertozzi教授联合创建的Firefly Bio公司正式亮相。获得9400万美元A轮融资资金后，Firefly Bio打算以其创新的蛋白降解偶联药物（DAC）平台为癌症疗法打开崭新的一页。Firefly的DAC平台结合了抗体偶联药物（ADC）和蛋白质降解剂各自的优势，同时克服了它们的缺陷以及两种模式结合时产生的潜在挑战。根据在实体瘤和血液肿瘤的临床前研究数据，单次使用Firefly的DAC即可在极低剂量下显著缩小肿瘤体积。“在过去的20年里，ADC的主要载荷一直是毒素，Firefly试图引入一种新的有效载荷类别，其效力与毒素水平相同，但可以更好地区分健康与疾病细胞。”Firefly新任首席执行官Scott Hirsch先生表示。他同时指出，如果Firefly能够成功开发DAC疗法，这将解锁ADC类别药物新的生物学机制。该公司目前将专注于开发实体瘤药物，日后有望扩展至免疫领域。2024年biotech合并第一案！先天免疫学领域重要企业“强强联手”1月23日，荷兰Oxitope Pharma和挪威Arxx Therapeutics宣布两家公司合并组成Calluna Pharma，新公司已经于A轮融资中筹募到7500万欧元。Calluna的新任首席执行官称此次合并为“两家先天免疫学领域的重要企业强强联手”。Oxitope致力于发现和开发治疗氧化应激引起的炎症和心血管疾病药物，主要产品是一款处于临床前阶段的、用于急性冠状动脉综合征（ACS）引起的心肌梗死（MI）再灌注损伤的抗体疗法。Arxx主要开发用于罕见纤维化疾病的疾病修饰疗法，2023年8月，其首款产品抗S100A4单克隆抗体AX-202开始双盲安慰剂对照试验。二者合并成立的Calluna将基于损伤相关分子模式（DAMP）的先天免疫领域的专业知识与一系列针对炎症和纤维化适应症的选择性抗体相结合，旨在满足由急性或慢性炎症和非溶解性组织纤维化引起的各种疾病的临床需求。迄今Calluna的研发管线中已经有四个潜力候选药物，包括：靶向S100A4的单克隆抗体CAL101，处于1期临床；可中和氧化磷脂的单克隆抗体CAL102，处于临床前。罕见病知名公司分拆！新锐推进AD新型基因疗法1月11日，Amlogenyx宣布完成5000万美元的A轮融资。Amlogenyx是由罕见病领域知名公司Ultragenyx分拆成立的子公司，是一家新型基因疗法开发公司，成立于2023年，目前专注于开发利用溶酶体酶治疗阿尔茨海默病的新型基因疗法。Ultragenyx曾透露，在对半乳糖唾液酸贮积症的研究中，发现一种被称为保护性蛋白/组织蛋白酶 A (PPCA) 的特定溶酶体化合物会影响β淀粉样蛋白。PPCA在C末端裂解β淀粉样蛋白并防止蛋白质在体外积聚；在阿尔茨海默病小鼠模型中，使用基于AAV的基因疗法将PPCA递送至溶酶体，3个月后淀粉样斑块减少了60%以上。此次融资将加速该疗法的研发。突破给药方式局限！口服大分子药物新锐获融资1月29日，奥礼生物宣布完成数千万元Pre-A轮融资，本轮融资将主要用于推进核心管线口服GLP-1制剂和生物药口服递送技术平台的构建。奥礼生物成立于2022年8月，创始团队来自于伦敦大学学院（University College London），在胃肠道生理学与药物吸收动力学等领域深耕多年。目前，该公司已开发数个口服多肽药物管线。据新闻稿介绍，大分子药物在临床中往往只能通过注射方式给药，因此有诸如全身药物暴露安全风险、患者接受治疗的场所限制、注射引起的患者依从性差等痛点。而通过口服递送吸收的方式或可解决上述难题。主打产品引进自中国！小分子靶向药新锐获融资2月1日，Graviton Bioscience宣布获得来自赛诺菲风险投资公司的战略投资，本轮融资将加速该公司卷曲螺旋形成蛋白激酶2（ROCK2）抑制剂的研发。Graviton Bioscience成立于2023年，专注于Rho/Rho相关ROCK2抑制剂研发，目前的适应症囊括中枢神经系统疾病、自身免疫性疾病、纤维化疾病等。该公司的主打候选药物GV101正处于1期临床研究阶段。值得一提的是，GV101是Graviton的前身FL2021-001公司自中国生物制药附属公司北京泰德制药引进的全新靶点、高选择性的ROCK2抑制剂，可通过高选择性地抑制ROCK2信号通路，发挥抑制纤维化进展、抗炎和免疫调节等多重作用，在肺纤维化、肝纤维化等领域具有较好的治疗潜力。该起授权交易总额逾5亿美元。读者们请星标⭐创鉴汇，第一时间收到推送免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文由药明康德内容团队根据公开资料整理编辑，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转发/复制至其他平台。转发授权请在「创鉴汇」微信公众号留言联系我们。更多数据内容推荐点击“在看”，分享创鉴汇健康新动态

抗体药物偶联物放射疗法细胞疗法siRNA

2024-03-13

·GoDesign

【一图看懂】2023年获FDA批准的小分子新药及药物设计思路

笔者根据美国FDA官网的公开信息，解读2023年获FDA药物评估和研究中心（CDER）批准上市的小分子药物，并总结了每个药物的分子结构、靶点/机制、研发公司，制作成图表。以下文字内容大多参考自FDA官方的药物说明书和分子结构图底下的参考资料。部分的数据除非特别引用，一般是参考维基百科和药企官方公告。小分子药物结构、机制与适应症汇总此前已介绍了上半年获批的小分子药物，请查看这篇文章：【一图看懂】2023上半年获FDA批准的小分子新药及药物设计思路10/12/2023: Velsipity (etrasimod)基本信息：Etrasimod是由Pfizer开发的1-磷酸鞘氨醇（S1P）受体调节剂，以高亲和力与S1P受体1、4和5结合，用于治疗成人中重度活动性溃疡性结肠炎（UC）。Etrasimod部分地、可逆地阻断淋巴细胞从淋巴器官流出的能力，减少外周血中淋巴细胞的数量。UC是一种自身免疫性疾病，影响北美和欧洲约380万人，症状包括出血和慢性腹泻、腹痛和失禁等。分子设计思路：首先通过内部HTS确定磺酰胺1是S1P1受体（EC50 = 6.7 nM）的有效激动剂。但芳基磺酰胺类似物在口服给药后不能有效降低小鼠的淋巴细胞计数。分别用吲唑和1,2,4-恶二唑取代苯环和磺酰胺，得到体内potency提高的分子2。随后，i）在吲唑环上引入酸性侧链，模拟S1P中发现的磷酸盐残基；ii）用二氢吲哚替换吲唑类环；iii）用氰基替换苯环的其中一个三氟甲氧基，发现二氢吲哚3在淋巴细胞降低实验中产生最大反应，将其作为lead。3对心脏表达的S1P3亚型的选择性（S1P3的激动会导致啮齿类动物心动过缓）非常好，且半衰期相对上市药物Fingolimod缩短明显（长达6-9天，停药后外周淋巴细胞水平恢复正常需要1-2个月），符合最初的优化目标。遗憾的是静脉输注24小时后，在大鼠大脑和脑脊液中检测不到4。提高CNS渗透性（可通过直接作用于星形胶质细胞上表达的S1P1来减少神经炎症）是进一步优化的重点。用甲氧基替换1,2,4-恶二唑linker，并对苯环的取代基进行优化得到上市药物Etrasimod，其相对于4得到改善的CNS暴露，脑-血浆（B/P）比率为1.9。图1. Etrasimod的药物设计。10/26/2023: Agamree (vamorolone)基本信息：Vamorolone是由Santhera开发的是糖皮质激素受体的部分激动剂（皮质类固醇），用于治疗2岁及以上的杜氏肌营养不良症 (DMD) 患者。美国的DMD患者约有11,000-13,000人，目前的标准治疗是皮质类固醇（尽管其存在严重的不良事件），大约70%的患者同时接受皮质类固醇治疗。DMD是最常见的肌营养不良症，是一种X连锁隐性遗传病（几乎只影响男性），其特征是DMD基因（人类基因组中最大的基因）发生突变，并且编码的肌营养不良蛋白丢失。DMD的特点是肌肉功能退化。患有这种罕见的致命疾病的患者会慢慢失去行走能力并出现呼吸衰竭，平均预期寿命低于30岁。分子设计思路：Vamorolone显然是皮质醇（氢化可的松）和泼尼松龙（1,2-脱氢皮质醇）的衍生物，结构上少了羟基，多了双键和甲基。Vamorolone多出来的双键已被证明可以去除与糖皮质激素受体的分子接触位点，并导致“解离”特性，即反式激活活性相对丧失，但保留反式抑制活性。反式激活引发了GR介导的药物活性的许多安全问题，而反式抑制则提高了抗炎功效。图2. Vamorolone的药物设计。11/8/2023: Fruzaqla (fruquintinib)基本信息： Fruquintinib（呋喹替尼）是由和黄医药开发（2023年1月以11.3亿美元授权给武田制药）的一款口服的高选择性、强效的VEGFR-1/2/3（IC50分别为33、35和0.5 nM，对其它激酶选择性较好）抑制剂，用于治疗既往接受过氟嘧啶、奥沙利铂和伊立替康治疗的转移性结直肠癌患者，包括既往接受过抗VEGF治疗和/或抗EGFR治疗（RAS野生型）的患者。在美国，2023年将诊断出约153,000例新发CRC病例，占所有新发癌症病例的7.8%。大约70%的CRC患者无论是在诊断时还是治疗后都会出现转移性疾病。分子设计思路：此前已有多款VEGFR抑制剂上市，其中市场表现最好的是Lenvatinib。如图3所示，呋喹替尼和Lenvatinib还是有不少相似之处。呋喹替尼主要改动的地方在杂环上多了一个N，以及用呋喃环替换了苯环上原有的极性侧链。图3. 部分上市的VEGFR抑制剂。11/15/2023: Defencath (taurolidine, heparin)基本信息：Defencath是由CorMedix开发的是牛磺罗定（taurolidine，噻二嗪类抗菌剂）和肝素（抗凝剂）的组合，用于降低通过中心静脉导管（CVC）接受血液透析 (HD) 的成年肾衰竭患者导管相关血流感染 (CRBSI) 的发生率。CRBSI在CVC患者中很常见。大约80%开始血液透析的患者将插入CVC以建立血管通路。每年使用CVC等血管内装置的患者会发生约250,000例CRBSI，导致约1/4的感染患者死亡。血液透析中的 CRBSI由多种病原体引起，其中许多病原体具有抗生素耐药性。分子设计思路：没找到牛磺罗定的药物发现文章。牛磺罗定源自内源性氨基酸衍生物牛磺酸。牛磺罗定在体内代谢为牛磺酸酰胺，最终生成牛磺酸和水，释放羟甲基，与细菌细胞壁中的胞壁蛋白以及内毒素和外毒素的氨基和羟基发生化学反应。该反应使细菌细胞壁的内毒素以及复杂的多糖和脂多糖成分变性，并使敏感的外毒素失活。图4. 牛磺罗定的抗菌机制。来源：PLoS ONE 2010, 5(1): e8927.11/15/2023: Augtyro (repotrectinib)基本信息：Repotrectinib是由BMS开发（2022年41亿美元收购Turning Point获得）的酪氨酸蛋白激酶（ROS1）抑制剂，用于治疗局部晚期或转移性ROS1阳性NSCLC成年患者。Repotrectinib是原癌基因ROS1和TRKA、TRKB和TRKC的抑制剂。包含ROS1结构域的融合蛋白可以通过下游信号通路的过度激活来驱动致瘤潜力，从而导致不受限制的细胞增殖。ROS1融合发生在约1-2%的NSCLC患者中。ROS1阳性肿瘤患者的平均年龄为50岁，往往比普通肺癌患者更年轻，其中女性多于男性，并且可能几乎没有吸烟史。ROS1阳性肺癌往往具有侵袭性，通常可扩散至大脑。分子设计思路：由于TRK激酶结构域的二次突变，总是会产生获得性耐药。TRKA中最常见的突变为G595R和G667C，分子模型表明， G595R突变引入了larotrectinib羟基吡咯烷基团的空间位阻（图5）。同样， G667C突变增加了larotrectinib的二氟苯基的空间位阻。为了克服上述耐药突变，开发了两种大环化合物LOXO-195和TPX-0005（即Repotrectinib），与larotrectinib的骨架相比，引入更大的构象刚性，并避免与R595和C667的空间clash。图5. Repotrectinib的药物设计。来源：J. Med. Chem. 2020, 63, 10726–10741.11/16/2023: Truqap (capivasertib)基本信息：Capivasertib是由阿斯利康开发的丝氨酸/苏氨酸激酶AKT（AKT1-3）的ATP竞争性抑制剂，与氟维司群联合用于治疗患有激素受体（HR）阳性、HER2阴性、患有一种或多种PIK3CA/AKT1/PTEN改变的局部晚期或转移性乳腺癌成年患者。PI3K-Akt-mTOR通路是人类癌症中最常失调的信号通路之一，已被证明可以介导对细胞毒性、抗激素和靶向治疗的耐药性。Akt是该信号通路中的关键节点。2020年，全球有超过200万患者被诊断患有乳腺癌，近685,000 死亡。HR阳性乳腺癌是最常见的乳腺癌亚型，超过65%的肿瘤是HR阳性且HER2低或阴性。PIK3CA、AKT1和PTEN突变影响高达50%的晚期HR阳性乳腺癌患者。分子设计思路：高通量的fragment虚拟筛选将氮杂吲哚1鉴定为PKB（即Akt）的ATP竞争性配体。该片段通过SBDD优化为6-苯基嘌呤2。用哌啶取代2中的苯基并引入4-氨基得到3（碱性胺与Glu和Asn分别形成盐桥和氢键）。为了与P-loop的亲脂口袋相互作用，引入芳香族基团，得到氯苯基取代的分子4。当用4-氯苄基替换4-氯苯基，得到的分子5对PKA的选择性提高至约30倍。但5具有高体内清除率和低口服生物利用度，需要进一步优化。尝试了不同位置的SAR，发现通过简单地在5的4-氨基哌啶引入4-酰胺（调整了pKa/溶解度），即可得到PK显著提高的分子6。然而，分子6对ROCK2激酶的选择性仅为5倍（ROCK2抑制剂已被证明可显著降低血压并导致心率和心肌收缩力增加），且对hERG的IC50达到5 μM。突破点在于苄基的α-碳取代，首先用碱性侧链取代，发现携带碱性基团的侧链会导致高清除率和低口服生物利用度；随后引入的中性尤其是含羟基（改善hERG抑制活性的常见策略）的侧链则显著提高了对ROCK2和hERG的选择性，最终得到上市药物Capivasertib。图6. Capivasertib的药物设计。11/27/2023: Ogsiveo (nirogacestat)基本信息：nirogacestat是由SpringWorks Therapeutics开发的口服γ分泌酶抑制剂，用于治疗需要全身治疗的进展性硬纤维瘤成年患者。硬纤维瘤是局部侵袭性和侵袭性软组织肿瘤，可导致严重的发病率。此外，当重要结构受到影响时，硬纤维瘤可能会危及生命。虽然硬纤维瘤不会转移，但现有的超适应症全身治疗通常难以治愈，并且手术切除后复发率高达77%。分子设计思路：没找到nirogacestat的药物发现文章。查阅文献nirogacestat应该是参考二肽类似物DAPT（Aβ IC50 = 20 nM）优化而来。图7.nirogacestat的药物设计。12/5/2023: Fabhalta (iptacopan)基本信息：旁路途径（AP）是补体激活的放大环，是各种人类疾病的促成因素，包括年龄相关性黄斑变性（AMD），阵发性睡眠性血红蛋白尿（PNH）等。AP的补体系统成分包括蛋白酶因子B (FB)和蛋白酶因子D (FD)等。FB是一种类胰蛋白酶丝氨酸蛋白酶，主要在肝脏和巨噬细胞产生，以潜伏形式在人体血液中循环。通过抑制FB可以阻断AP放大循环，用于治疗多种补体介导的疾病。Iptacopan是由诺华研发的FB抑制剂，用于治疗PNH。Iptacopan与补体旁路途径的FB结合，调节C3的裂解、下游效应子的产生以及末端途径的扩增。在PNH中，血管内溶血 (IVH) 由下游膜攻击复合物 (MAC) 介导，而血管外溶血 (EVH) 由C3b调理作用促进。Iptacopan在补体级联的替代途径中发挥近端作用，控制C3b介导的EVH和末端补体介导的IVH。分子设计思路：通过高通量筛选鉴定出氨基咪唑啉1（IC50 = 6.6 μM，SPR Kd = 10 μM)片段。考虑到萘环骨架不容易进行SAR，且萘基的非极性性质可能会使与相对极性的S1口袋很难产生positive的相互作用，用相对极性的吲哚环取代萘环。同时，用不同碱度的胺来替换咪唑啉，发现哌啶衍生物18的IC50为50 μM。18的结构简单（MW = 242.4），加上哌啶的C-2和C-4方便衍生化，从而提供新的SAR位点：1）在哌啶的2位引入苯基得到化合物19，其共晶结构显示哌啶的C-4位能够生长到S3口袋中；2）在哌啶的C-4位引入-OMe得到的21可以显著提高效力，还表现出α2c受体结合亲和力的显著降低 (IC50 = 11 μM)。值得一提的是，当21的苯基换为羟基，得到的哌啶29相比21效力提高了2倍。29与FB的共晶揭示了羟基和结晶缓冲液中的硫酸根离子之间的相互作用，与Arg192、Val218和Asn220B形成了复杂的氢键网络。为了进一步提高potency，尝试通过在哌啶的C-2位置引入极性官能团来模拟这种相互作用。重新评估了29和19与FB结合的晶体结构，发现19中苯环的对位位置完美，可以将取代基放入硫酸盐占据的空间中。在苯环对位连上羧酸，得到的35相比29的potency提高了近100倍。此外，酸的添加消除了hERG和肾上腺素能受体活性，但35在不同物种间存在功能活性差异。猜测填充S3口袋应该会增强对抗人类酶的效力，也可能导致小鼠效力随之增加。最后，在哌啶的C-4处用乙氧基替换甲氧基能更深地扩展到S3口袋，用吲哚C-5甲氧基替换甲基提供了更大程度的眼部AP抑制，最终得到上市药物iptacopan。图8. Iptacopan的药物设计。

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