更新于：2024-04-01

GR

糖皮质激素受体

更新于：2024-04-01

基本信息

别名

糖皮质激素受体、Glucocorticoid receptor、GR

+ [5]

简介

Has lower transcriptional activation activity than isoform Alpha. Exerts a dominant negative effect on isoform Alpha trans-repression mechanism (PubMed:20484466). Receptor for glucocorticoids (GC) (PubMed:27120390). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors (PubMed:28139699). Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Involved in chromatin remodeling (PubMed:9590696). Plays a role in rapid mRNA degradation by binding to the 5' UTR of target mRNAs and interacting with PNRC2 in a ligand-dependent manner which recruits the RNA helicase UPF1 and the mRNA-decapping enzyme DCP1A, leading to RNA decay (PubMed:25775514). Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth (By similarity). Has transcriptional activation and repression activity (PubMed:15866175, PubMed:19248771, PubMed:20484466, PubMed:23820903, PubMed:11435610, PubMed:15769988, PubMed:17635946, PubMed:19141540, PubMed:21664385). Mediates glucocorticoid-induced apoptosis (PubMed:23303127). Promotes accurate chromosome segregation during mitosis (PubMed:25847991). May act as a tumor suppressor (PubMed:25847991). May play a negative role in adipogenesis through the regulation of lipolytic and antilipogenic gene expression (By similarity). Acts as a dominant negative inhibitor of isoform Alpha (PubMed:7769088, PubMed:8621628, PubMed:20484466). Has intrinsic transcriptional activity independent of isoform Alpha when both isoforms are coexpressed (PubMed:19248771, PubMed:26711253). Loses this transcription modulator function on its own (PubMed:20484466). Has no hormone-binding activity (PubMed:8621628). May play a role in controlling glucose metabolism by maintaining insulin sensitivity (By similarity). Reduces hepatic gluconeogenesis through down-regulation of PEPCK in an isoform Alpha-dependent manner (PubMed:26711253). Directly regulates STAT1 expression in isoform Alpha-independent manner (PubMed:26711253). Increases activity of isoform Alpha. More effective than isoform Alpha in transcriptional activation, but not repression activity. Has transcriptional activation activity. Has transcriptional activation activity. Has highest transcriptional activation activity of all isoforms created by alternative initiation (PubMed:15866175, PubMed:23820903). Has transcriptional repression activity (PubMed:23303127). Mediates glucocorticoid-induced apoptosis (PubMed:23303127, PubMed:23820903). Has transcriptional activation activity. Has transcriptional activation activity. Has lowest transcriptional activation activity of all isoforms created by alternative initiation (PubMed:15866175, PubMed:23820903). Has transcriptional repression activity (PubMed:23303127). Has transcriptional activation activity.

关联

358

项与 GR 相关的药物

Vamorolone

靶点

作用机制

GR激动剂

在研机构

Santhera Pharmaceuticals Holding AG [+5]

原研机构

ReveraGen BioPharma, Inc. [+1]

在研适应症

杜氏肌营养不良症 [+1]

非在研适应症

肌萎缩侧索硬化 [+8]

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2023-10-26

Albuterol/Budesonide

沙丁胺醇/布地奈德

靶点

GR x β2-adrenergic receptor

作用机制

GR激动剂 [+1]

在研机构

AstraZeneca PLC [+3]

原研机构

阿斯利康制药有限公司

在研适应症

哮喘 [+2]

非在研适应症-

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2023-01-10

Lonapegsomatropin-tcgd

隆培促生长素

靶点

作用机制

GR激动剂

在研机构

Ascendis Pharma Endocrinology Division A/S [+3]

原研机构

Ascendis Pharma A/S

在研适应症

生长激素缺乏症 [+2]

非在研适应症

垂体性侏儒症

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2021-08-25

13,312

项与 GR 相关的临床试验

NCT06234345 / Not yet recruiting临床3期

Randomized, Open-label, Parallel, Active-controlled, Multicenter Study of Efficacy and Safety of Fixed-dose Combination of Fluticasone /Formoterol /Glycopyrronium for the Treatment of Patients With Chronic Obstructive Pulmonary Disease

Several studies have demonstrated the benefits of the LAMA (Long-Acting Muscarinic Antagonists) + LABA (Long-Acting Beta-Agonists) + IC (inhaled corticosteroids) combination in the treatment of chronic obstructive pulmonary disease (COPD). The use of the triple combination in patients with severe airflow obstruction and a history of flares has been associated with improved lung function, improved patient-reported endpoints and prevention of flares, when compared to LABA, LABA + LAMA and LABA + IC. Furthermore, when compared to dual therapies LABA + IC and LABA + LAMA, triple therapy has been able to reduce all-cause deaths among chronic obstructive pulmonary disease (COPD) patients.
Previously published studies have demonstrated that the triple combination of Fluticasone 250 mcg/Formoterol 12 mcg/Glycopyrronium 12.5 mcg was able to improve lung function in chronic obstructive pulmonary disease (COPD) patients with a history of flares. There was also a significant improvement in the mMRC (modified-Medical Research Council) which began in the 2nd week of treatment and continued up to week 12. The association was considered safe and well tolerated, with only mild to moderate adverse events recorded in approximately 25% of the subjects treated in the study.
Furthermore, bioavailability studies performed with the components of the combination proposed as experimental drug - Fluticasone/Formoterol/Glycopyrronium - indicated that there is no pharmacokinetic interaction between the 3 active ingredients when they were administered concomitantly to healthy individuals under fasting conditions.

开始日期2026-02-28

申办/合作机构

Eurofarma Laboratórios SA

NCT06243731 / Not yet recruitingN/A

Retrospective Chart Review of Safety Outcomes Associated With Use of Maribavir in Patients With Post-transplant Refractory Cytomegalovirus (CMV) Infection and Comorbid Endstage Renal Disease (ESRD) or Comorbid Severe Chronic Renal Disease Requiring Peritoneal Dialysis or Hemodialysis

The main aim of this study is to assess the safety profile of maribavir when treating refractory cytomegalovirus (CMV) infection after transplantation in adults with kidneys that are no longer functioning on their own (also called end-stage renal disease or ESRD) or have severe chronic kidney disease requiring artificial filtering of the kidney (dialysis) or the blood (hemodialysis).
In this study, already existing data will be collected from the participant's medical records. The study will only review data collected as part of the normal clinical routine and will not impact the standard medical care and treatment of participants.

开始日期2025-05-30

申办/合作机构

Takeda Pharmaceutical Co., Ltd.

NCT05726292 / Not yet recruiting临床2期IIT

A Randomized Phase II Trial of Neoadjuvant Enzalutamide Plus the Glucocorticoid Receptor Antagonist Relacorilant Versus Placebo for Patients With High-risk Localized Prostate Cancer

Researchers conducting this study hope to learn about the safety and effectiveness of combining two study drugs, relacorilant and enzalutamide, plus androgen deprivation therapy (ADT), also known as hormone therapy. This study is for individuals who have been diagnosed with advanced, high-risk prostate cancer and standard therapies available to treat your disease have not been effective. Participation in this research will last about 3 years and 9 months.

开始日期2025-04-01

申办/合作机构

The University of Chicago

100 项与 GR 相关的临床结果

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100 项与 GR 相关的转化医学

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0 项与 GR 相关的专利（医药）

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23,243

项与 GR 相关的文献（医药）

2024-03-25·Philosophical transactions of the Royal Society of London. Series B, Biological sciences

Modelling the role of glucocorticoid receptor as mediator of endocrine responses to environmental challenge.

Article

作者: Blanca Jimeno ; Juan G Rubalcaba

Glucocorticoid hormones (GCs) modulate acute 'stress' responses in vertebrates, exerting their actions across many physiological systems to help the organism face and overcome challenges. These actions take place via binding to the glucocorticoid receptor (GR), which determines not only the magnitude of the GC-mediated physiological response but also the negative feedback that downregulates GCs to restore homeostasis. Although GR function is assumed to determine GC regulation capacity, the associations between GR abundance and individuals' coping abilities remain cryptic. We developed a dynamic model fitted to empirical data to predict the effects of GR abundance on both plasma GC response patterns and the magnitude of GC-mediated physiological response. Individuals with higher GRs showed lower GC exposure, stronger physiological responses and greater capacity to adjust this response according to stressor intensity, which may be translated into more resilient and flexible GC phenotypes. Our results also show that among-individual variability in GR abundance challenges the detectability of the association between plasma GC measurements and physiological responses. Our approach provides mechanistic insights into the role of GRs in plasma GC measurements and function, which point at GR abundance fundamentally driving complex features of the GC regulation system in the face of environmental change. This article is part of the theme issue 'Endocrine responses to environmental variation: conceptual approaches and recent developments'.

2024-03-12·Neurology

Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial.

Article

作者: Utkarsh J Dang ; Jesse M Damsker ; Michela Guglieri ; Paula R Clemens ; Seth J Perlman ; Edward C Smith ; Iain Horrocks ; Richard S Finkel ; Jean K Mah ; Nicolas Deconinck ; Nathalie M Goemans ; Jana Haberlová ; Volker Straub ; Laurel Mengle-Gaw ; Benjamin D Schwartz ; Amy Harper ; Perry B Shieh ; Liesbeth De Waele ; Diana Castro ; Michele L Yang ; Monique M Ryan ; Craig M McDonald ; Mar Tulinius ; Richard I Webster ; Hugh J Mcmillan ; Nancy Kuntz ; Vamshi K Rao ; Giovanni Baranello ; Stefan Spinty ; Anne-Marie Childs ; Annie M Sbrocchi ; Kathryn A Selby ; Migvis Monduy ; Yoram Nevo ; Juan J Vilchez ; Andres Nascimento-Osorio ; Erik H Niks ; Imelda J M De Groot ; Marina Katsalouli ; John N Van Den Anker ; Leanne M Ward ; Mika Leinonen ; Andrea L D'Alessandro ; Eric P Hoffman

BACKGROUND AND OBJECTIVES:

Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone).

METHODS:

A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2.

RESULTS:

A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups.

DISCUSSION:

Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone.

TRIAL REGISTRATION INFORMATION:

ClinicalTrials.gov Identifier: NCT03439670.

CLASSIFICATION OF EVIDENCE:

This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.

2024-03-01·Biomedical reports

Andrographolide acts with dexamethasone to inhibit the growth of acute lymphoblastic leukemia CEM‑C1 cells via the regulation of the autophagy‑dependent PI3K/AKT/mTOR signaling pathway.

Article

作者: Xiaowen Li ; Tong Wu ; Weihong Chen ; Jiannan Zhang ; Yanping Jiang ; Jianzhi Deng ; Wenqing Long ; Xi Qin ; Yuehan Zhou

Acute lymphoblastic leukemia (ALL) is one of the most common malignant tumor types of the circulatory system. Dexamethasone (DEX) acts on the glucocorticoid (GC) receptor (GR) and is a first-line chemotherapy drug for ALL. However, long-term or high-dose applications of the drug can not only cause adverse reactions, such as osteoporosis and high blood pressure, but can also cause downregulation of GR and lead to drug resistance. In the present study, reverse transcription-quantitative PCR, western blotting and LysoTracker Red staining were used to observe the effects of DEX and andrographolide (AND; a botanical with antitumorigenic properties) combined treatment. It was found that AND enhanced the sensitivity of CEM-C1 cells, a GC-resistant cell line, to DEX, and synergistically upregulated GR both at the transcriptional and post-transcriptional level with DEX. The combination of AND with DEX synergistically alkalized lysosomal lumen and downregulated the expression of autophagy-related genes Beclin1 and microtubule-associated 1 protein light chain 3 (LC3), thereby inhibiting autophagy. Knocking down LC3 expression enhanced GR expression, suggesting that GR was regulated by autophagy. Furthermore, compared with the monotherapy group (AND or DEX in isolation), AND interacted with DEX to activate the autophagy-dependent PI3K/AKT/mTOR signaling pathway by enhancing the phosphorylation of PI3K, AKT and mTOR, thereby decreasing GR degradation and increasing the sensitivity of cells to GCs. In conclusion, the present study demonstrated that AND exhibited a synergistic anti-ALL effect with DEX via upregulation of GR, which was orchestrated by the autophagy-related PI3K/AKT/mTOR signaling pathway. The results of the present study therefore provided novel research avenues and strategies for the treatment of ALL.

106

项与 GR 相关的新闻（医药）

2024-03-21

·药明康德

前沿 | 精准抗炎！艾伯维开发全新ADC登《科学》子刊

▎药明康德内容团队编辑糖皮质激素是治疗多种炎症性疾病的有效药物，但由于糖皮质激素的作用往往是全身性的，一旦接受治疗的时间过长，患者就可能遭遇骨折、血糖升高、青光眼等严重副作用。因此，糖皮质激素治疗的给药剂量和持续时间受到限制。如果能选择性靶向发炎组织发挥作用，糖皮质激素的临床应用将得到极大的提升。在一项发表于《科学-转化医学》的研究中，艾伯维生物研究中心的研究团队设计了一种名为ABBV-3373的抗体偶联药物，解决这一问题。ABBV-3373将抗肿瘤坏死因子（TNF）抗体与增强糖皮质激素受体活性的化合物偶联，其中TNF是在免疫细胞表面活跃的蛋白质。这样的设计使得偶联物在被摄入细胞之前，会与过度活跃的免疫细胞上的TNF结合，释放糖皮质激素受体调节剂以平息细胞的炎症活动。▲ABBV-3373的结构和特性（图片来源：参考资料[1]）在小鼠实验中，ABBV-3373可有效抑制患有接触性超敏反应或诱发关节炎的小鼠的炎症信号传导，并且单剂量即可完全抑制关节炎超过30天。此外，对健康志愿者的1期临床试验证实了ABBV-3373的药物代谢动力学特征，并且没有显著影响志愿者糖皮质激素的全身标记物。这一结果为克服糖皮质激素临床使用中的主要安全障碍铺平了道路，支持了其作为更安全、更可持续的抗炎工具的潜力。参考资料：[1] McPherson et al. An anti–TNF–glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases. Science Translational Medicine (2024). DOI: 10.1126/scitranslmed.add8936本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。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。大家都在看▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放

临床1期抗体药物偶联物

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。

上市批准临床3期申请上市

2024-03-10

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《癌细胞》：慢性压力设下癌症转移“陷阱”！科学家发现，慢性压力会促使中性粒细胞释放NET，塑造有利癌症转移的微环境

*仅供医学专业人士阅读参考生活中的压力无孔不入。要说如今人类所共同面对的压力，恐怕就是日益飞速进展的AI技术吧。哦对，还有前些天考研出分了，不管结果如何，祝同学们能够摆脱考研的压力。适当的压力促使人进步，而过度的慢性压力则是慢性毒药，危害记忆、认知、行为以及心血管、胃肠道、免疫系统，使人憔悴不堪。近日一篇发表在Cancer Cell期刊上的最新论文更是提出，慢性压力还会使得我们的免疫卫士中性粒细胞负能量满满，反倒打造出促进肿瘤转移的温床[1]。美国冷泉港实验室的Mikala Egeblad团队发现，慢性压力诱导机体释放的糖皮质激素，会改变中性粒细胞的正常昼夜节律，并促使其释放一种称为中性粒细胞胞外陷阱（NET）的结构，从而构成有助于肿瘤细胞转移的微环境。使用酶减少NET水平，能够减少乳腺癌细胞向小鼠肺部转移。论文首页截图已有的研究表明，慢性压力会激活下丘脑-垂体-肾上腺轴，导致糖皮质激素（人类皮质醇和小鼠皮质酮）的释放。糖皮质激素与其受体结合后通过调节基因表达，参与促进肿瘤转移，被证明与患者癌症转移风险增加和生存率低相关。果不其然，在这项研究中，Mikala Egeblad团队采用两种慢性压力小鼠模型发现，相较于对照组，慢性压力下，乳腺癌小鼠不仅皮质酮水平提高，且肿瘤大小明显增加约1倍，转移水平增加2-4倍。这些结果在肺癌、胰腺癌小鼠模型中得到验证。慢性压力诱发小鼠肿瘤转移进一步研究表明，注射皮质酮同样能够增加小鼠的肿瘤转移负担，说明慢性压力确实借糖皮质激素之手促进肿瘤转移。但是利用基因编辑敲除肿瘤细胞上的相应受体，研究者们发现，慢性压力能够促肿瘤转移，并非是直接作用于肿瘤细胞的结果。那么，慢性压力到底在迫害谁？研究者们将目光投向诸位免疫细胞。结合小鼠实验和RNA-seq技术，他们观察到，暴露于慢性压力或者补充糖皮质激素（地塞米松）会诱发乳腺癌小鼠的肺部免疫微环境发生变化，T细胞、自然杀伤细胞、活化巨噬细胞的浸润减少；相反，中性粒细胞浸润增加，招募中性粒细胞的趋化因子基因Cxcl2、Cxcl5表达水平提高。又借助糖皮质激素受体激动剂（GSK9027）和基因编辑技术，研究者们找到了慢性压力的真正受害者——中性粒细胞。具体来看，糖皮质激素与中性粒细胞上相应受体的结合，会诱导中性粒细胞中与昼夜节律以及氧化应激反应相关的基因失调，导致关键时钟基因Per1的表达上调。这一系列操作，致使中性粒细胞表型改变，表现出异常的衰老表型，细胞内活性氧化物（ROS）水平提高，从而倾向于形成一种名为中性粒细胞胞外陷阱（NET）的结构。慢性压力诱导中性粒细胞释放NET，敲除中性粒细胞的糖皮质激素受体可以消除这种效应NET是由中性粒细胞释放的网状结构，包含DNA、组蛋白和各种蛋白酶。NET本是中性粒细胞用来应对病原体感染的手段，但近年来的研究表明，对于肿瘤细胞来说，NET是个非常适合附着和生长的微环境，有助于促进肿瘤细胞迁移、侵袭。简而言之，慢性压力倒不是在敦促肿瘤细胞日思进取，而是压迫中性粒细胞“生物钟紊乱”，聚在肺部等部位释放出NET，为肿瘤细胞的到来铺好了床。机制不仅是荷瘤小鼠，研究者们发现，慢性压力也会导致健康小鼠的肺部和血浆中NET水平提高。如果使用能够消化NET的酶DNase I治疗，可有效降低慢性压力下健康小鼠的NET水平，减少肺部纤连蛋白沉积，而不影响中性粒细胞浸润。对于暴露于慢性压力的荷瘤小鼠，DNase I治疗可以显著减少乳腺癌向肺部转移或胰腺癌向脾脏转移，有效抑制转移部位的肿瘤细胞增殖。 DNase I治疗减少肺转移最后，研究者们将小鼠实验得到的结论转化到临床上。他们发现，肿瘤具有慢性压力相关基因表达特征的乳腺癌患者总生存率更低，尤其是ER+/PR+乳腺癌患者；与HER2+或三阴性乳腺癌患者的总体生存率之间的相关性未达到显著水平。 NET水平与患者预后相关相比于常人，癌症患者承担着更为严重的慢性压力，包括对疾病预后的担忧、长期的治疗过程以及与疾病相关的社会经济负担等。这项研究结果强调，减轻癌症患者的压力应该成为疗程重要组成部分。此外，当前糖皮质激素类药物被广泛用于缓解化疗的副作用以及晚期癌症的治疗，但此次小鼠实验提供充分证据表明，糖皮质激素能够促进肿瘤转移并降低治疗反应，应进一步评估其在癌症治疗中的应用。还是那句话，适当排解压力，莫要在不知不觉中陷于慢性压力中。不然，连中性粒细胞都要被摧残得不分昼夜，满脑子都是释放NET。参考文献：[1]https://www.sciencedirect.com/science/article/pii/S1535610824000370本文作者丨张艾迪