A 2-Part, Open-label, Non-randomized (Part A) and Randomized, Double-blinded, Placebo-controlled (Part B) multicentric, international study with adaptive design to evaluate safety and tolerability of bazedoxifene, concentrated solution for nebulization (BAZE-X1) in addition to Standard of Care in hospitalized COVID-19 patients suffering from moderate to severe Pneumonia.

开始日期2022-01-19

申办/合作机构-

NCT04821141 / Recruiting临床2期IIT

Randomized IIB Study of the Effect of Bazedoxifene Plus Conjugated Estrogens on Breast Imaging and Tissue Biomarkers in Peri or Post-Menopausal Women at Increased Risk for Development of Breast Cancer

Women at risk for development of breast cancer and experiencing vasomotor menopausal symptoms (hot flashes) will be randomized to bazedoxifene (BZA) plus conjugated estrogens (CE) for 6 months versus a wait list control. Two risk factors for development of breast cancer will be studied pre-study and after 6 months: fibroglandular volume (FGV) on mammogram as assessed by Volpara software and proliferation by Ki-67 immunocytochemistry in benign breast tissue acquired by random periareolar fine needle aspiration (RPFNA). Change in biomarkers will be compared between groups.

开始日期2021-12-14

申办/合作机构

University of Kansas

[+1]

EUCTR2021-000320-35-CZ / Not yet recruiting临床2期

Open label, monocentric pilot study to evaluate safety and efficacy of Bazedoxifene in addition to Standard of Care in hospitalized COVID-19 patients suffering from moderate to severe Pneumonia

开始日期2021-03-05

申办/合作机构-

100 项与醋酸巴多昔芬相关的临床结果

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100 项与醋酸巴多昔芬相关的转化医学

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100 项与醋酸巴多昔芬相关的专利（医药）

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项与醋酸巴多昔芬相关的文献（医药）

2024-01-02·Scandinavian journal of rheumatology

Treatment with a tissue-selective oestrogen complex does not affect disease pathology but reduces pre-BI cells in lupus-prone mice

Article

作者: Nordqvist, J ; Islander, U ; Drevinge, C ; Scheffler, J M ; Carlsten, H ; Engdahl, C

OBJECTIVE:

Systemic lupus erythematosus (SLE or lupus) is an autoimmune disease characterized by B-cell dysfunction, production of autoantibodies, and immune complex formation. Lupus is overrepresented in females, indicating that sex hormones play a role in the pathophysiology. Treatment with a tissue-selective oestrogen complex (TSEC) containing conjugated oestrogens and the selective oestrogen receptor modulator bazedoxifene (BZA) protects against postmenopausal vasomotor symptoms and osteoporosis, but its impact on organ damage in lupus is not fully understood.

METHOD:

We used ovariectomized MRL/lpr mice, treated with two different physiological doses of 17β-oestradiol-3-benzoate (E2), BZA, or TSEC (E2 plus BZA), to assess early and late B-cell development and to determine histological disease manifestations in the kidneys and salivary glands.

RESULTS:

TSEC treatment reduced the frequency of the pre-BI population in bone marrow to levels equivalent to treatment with physiological doses of E2 alone but did not affect any of the other examined B-cell populations. Our earlier studies indicated that TSEC treatment did not aggravate disease development in ovariectomized MRL/lpr mice, while protecting against trabecular bone loss. Here, we follow up on our previous study and show that neither ovariectomy alone nor TSEC treatment of ovariectomized MRL/lpr mice influenced perivascular lymphocyte infiltration to the kidneys or salivary glands.

CONCLUSION:

TSEC does not aggravate a mouse model of lupus, when given in doses that protect against postmenopausal lupus-associated bone loss. This indicates that further investigations into TSEC as a treatment for osteoporosis or vasomotor symptoms in postmenopausal women with SLE are warranted.

2024-01-01·Journal of pediatric hematology/oncology

Bazedoxifene Suppresses the Growth of Osteosarcoma Cells by Inhibiting IL-6 and IL-11/GP130 Signaling Pathway

Article

作者: Wu, Xiaojuan ; Cao, Yang ; Xiao, Hui ; Feng, Jiexiong ; Lin, Jiayuh

Osteosarcoma is the most common primary bone tumor. Using the multiple ligands simultaneous docking method, we found that bazedoxifene could bind to the GP130 D1 domain. We then demonstrated that bazedoxifene can decrease cell viability and cell migration of osteosarcoma cells by inhibiting interleukin 6 (IL-6) and IL-11/GP130 signaling. Consistently, treatment with IL-6 or IL-11 antibody or knockdown of GP130 by siRNA silenced the activation of STAT3, ERK, and AKT. Similarly, recombinant IL-6 and IL-11 proteins antagonized the inhibitory effect of bazedoxifene on osteosarcoma cells. Finally, the combinational treatment of temsirolimus and bazedoxifene synergistically suppressed osteosarcoma development in vitro and in vivo. Our findings suggest that bazedoxifene directly prompts the deactivation of GP130 and inhibits the osteosarcoma progression in vitro and in vivo. Therefore, bazedoxifene could be effectively applied as a therapeutic drug for human osteosarcoma in the future.

2024-01-01·Phytomedicine : international journal of phytotherapy and phytopharmacology

Breast cancer cells are sensitized by piperine to radiotherapy through estrogen receptor-α mediated modulation of a key NHEJ repair protein- DNA-PK

Article

作者: Shaheer, Koniyan ; Prabhu, Br Swathi ; Lakshmanan-M, Divya ; Ali, H Shabeer

BACKGROUND:

Non-homologous end joining, an important DNA-double-stranded break repair pathway, plays a prominent role in conferring resistance to radiotherapeutic agents, resulting in cancer progression and relapse.

PURPOSE:

The molecular players involved in the radio-sensitizing effects of piperine and many other phytocompounds remain evasive to a great extent. The study is designed to assess if piperine, a plant alkaloid can alter the radioresistance by modulating the expression of non-homologous end-joining machinery.

METHODS AND MATERIALS:

Estrogen receptor-positive/negative, breast cancer cells were cultured to understand the synergetic effects of piperine with radiotherapy. Cisplatin and Bazedoxifene were used as positive controls. Cells were exposed to γ- radiation using Low Dose gamma Irradiator-2000. The piperine effect on Estrogen receptor modulation, DNA-Damage, DNA-Damage-Response, and apoptosis was done by western blotting, immunofluorescence, yeast-based-estrogen-receptor-LacZ-reporter assay, and nuclear translocation analysis. Micronuclei assay was done for DNA damage and genotoxicity, and DSBs were quantified by γH2AX-foci-staining using confocal microscopy. Flow cytometry analysis was done to determine the cell cycle, mitochondrial membrane depolarization, and Reactive oxygen species generation. Pharmacophore analysis and protein-ligand interaction studies were done using Schrodinger software. Synergy was computed by compusyn-statistical analysis. Standard errors/deviation/significance were computed with GraphPad prism.

RESULTS:

Using piperine, we propose a new strategy for overcoming acquired radioresistance through estrogen receptor-mediated modulation of the NHEJ pathway. This is the first comprehensive study elucidating the mechanism of radio sensitizing potential of piperine. Piperine enhanced the radiation-induced cell death and enhanced the expression and activation of Estrogen receptor β, while Estrogen receptor α expression and activation were reduced. In addition, piperine shares common pharmacophore features with most of the known estrogen agonists and antagonists. It altered the estrogen receptor α/β ratio and the expression of estrogen-responsive proteins of DDR and NHEJ pathway. Enhanced expression of DDR proteins, ATM, p53, and P-p53 with low DNA-PK repair complex (comprising of DNA-PKcs/Ku70/Ku80), resulted in the accumulation of radiation-induced DNA double-stranded breaks (as evidenced by MNi and γH2AX-foci) culminating in cell cycle arrest and mitochondrial-pathway of apoptosis.

CONCLUSION:

In conclusion, our study for the first time reported that piperine sensitizes breast cancer cells to radiation by accumulating DNA breaks, through altering the expression of DNA-PK Complex, and DDR proteins, via selective estrogen receptor modulation, offering a novel strategy for combating radioresistance.

项与醋酸巴多昔芬相关的新闻（医药）

2024-05-24

·精准药物

PROTACs、分子胶等靶向降解剂（TPD）的高通量筛选

侃言诱导邻近，利用小分子诱导“蛋白质对”接近，是一种创新的药物发现模式。例如之前分享的Revolution Medicine开发的KRAS特异性和泛KRAS抑制剂RMC-6291、RMC-9805、RMC-6263等，作为一种分子胶而非双功能分子，通过诱导伴侣亲环蛋白和靶标蛋白形成三元复合物，降解靶标，进而干扰靶标上下游信号，详见👉 🔗。邻近诱导物，最常见的除了分子胶（MGs）以外，还有双功能分子（PROTACs）。本次分享，结合近几年来自学术界和CRO技术服务公司几篇前沿性研究文章，介绍一种高通量发现邻近诱导物（PROTACs & 分子胶）的高效、快速地方法——DNA编码化合物库筛（DEL）选技术。因此，本次主要分享以下3点：1、邻近诱导物：分子胶和PROTACs2、DEL与邻近诱导3、DEL应用于邻近诱导物发现的实例①ERα，by X-Chem, J Med Chem (2021)②BRD4, by HitGen, ACS Chem Biol (2023)③BRD9, by Broad Institute, J Am Chem Soc (2023)④BRDx, by Broad Institute, Nat Chem Bio (2024)⑤BRD4, by HK Univeristy & SIMM, ChemRxiv (2024)01邻近诱导化合物：MGs & PROTACs蛋白靶向降解剂（TPD）作为邻近诱导的实际应用备受关注，其中最常见的为分子胶（MGs）、和靶向蛋白降解嵌合体（PROTACs）。不同于靶标抑制剂，TPD不一定需要对蛋白有抑制活性，只需要对其有亲和力。因此，TPD可适用于更加广泛的靶标类别，甚至包括传统意义上被认为是“不可成药”的靶标，以及支架蛋白靶标、突变蛋白靶标等。分子胶（MGs）是一种邻近依赖性单价分子，通过粘合两个蛋白发挥作用。其作用的模式（MOA）可能为以下三种：1、MGs显著增强POI与E3的相互作用；2、MGs结合到POI，然后被E3识别；3、MGs结合到E3连接酶，然后识别新的底物POI。分子胶普遍存在，是一种理想的蛋白降解剂。然而关于其合理地发现和在药物治疗中的应用，非常具有挑战性。这些化合物大都是偶然发现的。通常是在表型分析中发现的化合物通过作用机制研究，发现的分子胶机理。关于其合理的设计、快速、高通量的筛查，将会非常具有吸引力！靶向蛋白降解嵌合体（PROTACs）是一种双特异性功能分子。一般，PROTACs由三部分组成：POI结合物、E3连接酶配体、以及连接两个分子的合适的连接子。PROTACs能招募目标蛋白（POI）和E3连接酶，诱导POI的多泛素化，使之随后被蛋白酶体介导降解。近些年最盛行的一种PROTACs开发方法是将抑制剂和已知的E3连接酶结合分子用适当的连接子连接起来。因此，一种快速、高效的筛查POI抑制剂的方法，发现潜在POI抑制剂，也非常具有吸引力。这里筛查出来的苗头化合物甚至不需要证明其抑制活性，仅仅具有亲和结合力就好。然后应用于PROTACs分子的形成和降解评估。以上两种邻近诱导物的合理设计和发现让人不禁想到了一种技术——基于亲和力筛选的DNA编码化合物库（DEL）筛选技术！02DEL与邻近诱导DNA编码化合物库（DEL）筛选技术本质上是一种亲和力结合实验。DEL筛选技术通过连接子连接DNA片段和潜在的POI结合物，构建多样性化合物文库，然后通过多轮生物淘选，从大量文库中分离出对POI具有亲和力的结合物，并通过对连接子连接的DNA片段测序鉴定、并解析结合物结构。因此，DEL筛选出来的苗头化合物对POI一般具有亲和力，但不一定具有抑制活性，需要后续进一步的体外/体内的活性鉴定。然而，TPD不一定需要像抑制剂那样的抑制功能效应，只需要亲和力！这不巧了嘛！一方面，DEL挑选的苗头化合物可以无缝地整合到嵌合分子中，应用于降解剂的降解能力评估。具体的操作，即，将DEL筛查出来的苗头化合物重合成，用反应性连接子一边连接苗头化合物，另一边用E3连接酶配体代替DNA片段，形成PROTACs分子。可以快速的探索数十、数百种由E3连接酶配体、连接子、POI结合物构成的组合，直接测定他们蛋白降解能力。快速、高效！接下来的实例中会谈到具体的应用。另一方面，也可以通过DEL技术，直接合成包含POI潜在结合物、连接子、E3连接酶配体的多样性文库，用于靶标和E3连接酶的筛选，直接筛查POI潜在结合物、以及连接子的多样性。或者，还可以对E3连接配体的多样性进行筛查。也有实际的应用报道在接下来的实例分享中具体说明。此外，分子胶是诱导邻近比较前沿的应用，它可能具有更加明显地优势，如更低地分子量、更少地可旋转键、更好地代谢稳定性等。然而，发现新型分子胶是比较具有挑战性的，而DEL广泛的化学空间，基于亲和力的生物淘选原理，为更加有潜力的分子胶的发现提供了无限可能。近两年，关于PROTACs和分子胶都有基于DEL的高质量、高档次文章报道，有来自企业界的技术服务公司，也有来自学术界的高等院校和研究所。接下来汇总了目前已报道的实例！03DEL应用于邻近诱导的实例鉴于邻近诱导物开辟了一种革新的药物治疗策略，合理的设计、和发现邻近诱导物就至关重要。学术界和企业界的CRO服务公司共同在此方面做出了不俗的贡献，开发出了两种靶向降解剂的发现策略：一是发现POI亲和力苗头化合物，用于PROTACs分子的生成；二是直接构建包含POI潜在结合物、连接子、E3连接酶配体的化合物文库，直接用于POI的筛查。Case / 01ERα : PROTACsby X-Chem2021年，X-Chem在J Med Chem上报道了其采用第一种方案，利用DNA编码化合物库筛选鉴定出了雌激素受体α（ERα）新型双特异性降解剂。ERα是雌激素受体的两种主要亚型之一，在约70%的乳腺癌中过度表达。如上图，是X-Chem研究人员从庞大的DEL文库筛选出苗头化合物，再到产生PROTACs组合的流程：首先，选择的文库是一个包含44个文库，约1,200亿个DEL分子（1.2x1012）的超级化合物库池子；POI（ERα）通过亲和tag固载，通过两轮生物淘选（洗涤和洗脱），富集到的DEL分子热洗脱后，对其DNA序列进行PCR扩增、测序。再通过“Click”偶联将富集的POI结合物与一些列E3连接酶配体连接起来，产生出PROTACs的组合。DEL筛选过后，从44个文库组成的池子中共产生了5.28亿次单端读取数据，每个文库每个筛选条件平均产生120万次读取。上表是从DEL中筛查出的苗头化合物，并对DNA片段的替代物进行了优化（2-7）筛查，以期寻找到合适的PROTACs连接子。研究人员首先以已知的POI结合物巴多昔酚作为模板，验证CRBN、VHL、IAP等作为E3配体的活性，最终确定VHL配体模型的降解潜力。之后，重点放在了以VHL作为E3配体，和DEL中筛查出来的苗头化合物组合在一起，生成了一系列PROTACs分子（化合物17-23，三个系列：酰胺连接、苯氧连接、酰胺连接的差向异构对照）。并对靶标、及包靶标的细胞进行了活性检测。酰胺连接的化合物都表现出了个位数nM级别的细胞降解潜力（ED50），单其结合力随着连接子的增长而减弱2-5倍（化合物17、18、19）。然而，对于苯氧连接子形成的PROTACs分子结合力的情况却相反，降解能力也不如酰胺键连接。这些化合物还与突变体D538G、S463P和Y537S进行了相应的结合实验，并显示出在野生型的20倍范围内的泛抑制作用。在细胞活力实验中，所有化合物都被证明是拮抗剂。从两个系列中选择出最具潜力的降解剂化合物18、21，进行后续MOA验证。生物化学上，这两种化合物在WT和突变体ERα FP结合试验中都非常有效！Case / 02BRD4: PROTACsby HitGen2023年，HitGen在ACS Chem Biol上报道了其采用第二种方案，利用DNA编码化合物库直接构建PROTACs文库，并针对BRD4，筛选出来新型PROTACs三元复合物。操作流程如下图：研究人员以三官能团支架分子作为连接子，一端连接DNA编码序列、一端连接E3连接酶配体、还有一端连接POI潜在配合物（通过两个循环构建潜在多样性配合物），并选择一端不连接E3连接酶配体的文库作为对照研究人员在筛选阶段对POI和E3连接酶与DEL文库孵育的方式进行控制，经过生物淘选、测序、数据分析，最终获得了具有针对BRD4有效降解的靶向降解剂。DEL文库：为了减少如方案1中大量繁琐的优化，HitGen研究人员通过构建包含E3连接酶配体的编码PROTACs文库，针对POI和E3 ligase直接进行筛选。如上图，PROTACs文库和对照组文库多样性相同，都包含628.6万个DEL分子。其中，选用了16个三官能团的支架分子作为连接子。筛选方案：如上图，研究人员设计了4个平行筛选方案，通过两轮筛选。方案一，用GST-tag标记BRD4，His-Tag标记CRBN/DDB1。将DEL文库、同POI、以及E3连接酶在溶液中共孵育；两轮筛选；第一轮孵育后通过亲和力GST-tag固载POI（BRD4），洗涤、热洗脱后的部分作为下一轮的input，与新鲜的亲和力tag标记的POI、E3连接酶进行第二轮共孵育，然后通过亲和力His-tag固载E3连接酶，洗涤、热洗脱，进入PCR扩增、NGS测序。目的是鉴定出同时结合POI、和E3连接酶的结合物。方案二，操作同方案一，但共孵育时不加入GST-tag标记的POI，而仅以GST-tag代替。目的是鉴定筛选背景。方案三，操作同方案一，但POI与E3连接酶不同时与文库共孵育。两轮筛选，第一轮仅GST-tag标记的POI与文库共孵育；二轮轮仅His-tag标记的E3连接酶与第一轮的热洗脱部分共孵育。目的是对照方案一，鉴定出具有协同作用的结合物。方案四，操作同方案一，但第一轮共孵育时不加入POI、E3连接酶，仅加入GST-Tag与文库共孵育。第二轮仅加入His-tag标记的DDB1进行共孵育。目的是鉴定筛选背景。筛选数据分析：如上图放大后的立方图。A代表PROTACs文库，B代表对照文库。筛选过后，对NGS数据进行去噪反褶积、形成可视化立方图。图中的点的大小与与序列读取数成正比。对比A中4个筛选条件下对PROTACs文库结合物富集的信息，可以看出，方案一的双靶标同时孵育获得明显的富集、方案三的协同孵育获得了中度的富集。因此，PROTACs的协同作用对信号富集具有加强的效应！对比方案一，A与B立方图表中PROTAC文库比对照组获得更明显的富集，也再次证明了PROTAC的协同作用对富集效应的加强。重合成验证：如下图，通过从DEL1323-1-13-311-348截获的三个线性特征中选择了9个具有代表性的PROTACs分子进行off-DNA重合成，以更好地了解结构、序列读数、和三元络合物形成的相关性。9个重合成的PROTACs分子分别代表着对连接子（R1)、POI结合物片段1（R2）、POI结合物片段2（R3）等不同位置的多样性选择。上表中，针对9个重合成的化合物，PROTACs文库在方案一与方案三中的序列读数的比值（S1/S3），反映了在E3连接酶在存在与不存在时，PROTACs分子结合POI的协同性。（备注：双功能分子结合两个蛋白的很大程度上不是非协同的吗？？？α~1 or < 1。只能说他们具有一定协同性，而非如分子胶的超强协同性，即分子胶只有在靶蛋白和呈递蛋白同时存在时才会对靶标有效结合，下面分子胶的筛选将会详细展开）在方案一中，DEL1323-1与DEL1323-3的序列读数的比值，反映了与CRBN通过沙利度胺片段促进的结合具有协同性。通过分析，两个最优的PROTACs分子cpd 1、cpd 5具有更高、更宽的曲线（上图曲线），以及通过比较另一种蛋白不存在和不存在时的抑制活性，也观察到α >1的正协同作用如下表。两个化合物针对BRD4的抑制活性IC50，在不添加CRBN/DDB1的情况下，IC50在次μM范围波动，添加CRBN/DDB1后，IC50均降至两位数nM范围，IC50比值在3左右。对于CRBN/DDB1，BRD4存在时IC50也降低2-4倍（上表）。综上所述，α值大于1，表明CRBN/DDB1和BRD4在三元配合物形成中具有积极的协同作用，这与CRBN/DDB1和BRD4同时存在时，信号比单独使用该蛋白筛选时强得多的选择结果相映衬。构效关系分析：通过对三个方向性片段的构效关系分析，也证明了DEL筛选序列的读数直接反映了DEL文库中PROTACs分子的相对三元复合物招募能力！这篇研究意义非凡！证明了利用DEL技术进行PROTACs文库设计、合成、和双蛋白亲和筛选，以直接发现针对BRD4的PROTACs分子的可行性。该方法解决了PROTAC发现和优化的基本操作：PROTAC与POI、E3连接酶的协同结合，以及连接子对协同结合的影响。通常这些都是最具挑战性的，因为有多种因素有助于降解过程。重要的是，这种筛选策略可以应用于需要关键正向协同性的分子胶的发现！非常巧合！同年来自MIT和哈弗Broad研究所的Stuart教授，在J Am Chem Soc上几乎用同样的策略，不过选用的是VHL配体作为E3连接酶结合物，针对BRD4同家族的BRD9进行DEL 分子胶文库的筛选。Case / 03BRD9 ：分子胶by Broad Institute of MIT and Harvard双功能分子与它们的两个蛋白质靶标在很大程度上是非协同的（协同因子α ~ 1，其中α = 解离常数(KD)二元/三元，下图）。因此，表现出钩效应——即高化合物浓度时，三元复合物消失，这是由于化合物与蛋白质1：1时，导致二元复合物失活。相比之下，分子胶表现出高协同性(α ≫ 1)，这有利于三元复合物的形成，尽管对蛋白质伴侣缺乏二元亲和力，从而减轻了钩效应。通常，化合物诱导的邻近促使两种蛋白联系起来：其中的靶蛋白用于调节信号，其中的呈递蛋白用于对靶蛋白附加功能效应。组织特异性、或细胞特异性的呈递蛋白使分子胶具有高选择性。因为，只有靶蛋白和呈递蛋白同时存在时，分子胶才会产生有效的结合！双功能分子，如PROTACs，由于连接器连接两个结合体设计理念，更容易产生。相比而言，分子胶虽更具有治疗上的优势，但是关于其设计更具有挑战性！关于其诱导蛋白的作用机制，更是多来自于偶然的发现。因此，从外部结构特征上来看，PROTACs具有明显的“结合物-连接子-结合物”的结构模式，而分子胶的特点非在结构上，而是在其诱导蛋白-蛋白结合方面的高协调性！分子胶化合物库设计和筛选：如下图，Stuart教授设计了一个“DNA标签-VHL配体-POI结合物”模式的DNA编码VHL邻近诱导化合物库，VHL CIP-DEL。文库包含94万分子。这里的新颖的地方是，E3配体和POI结合物与DNA编码片段在一个线性上，而不再如PROTACs文库的支线结构。VHL可以看作是POI结合物组成的一部分；多样性POI结合物组成也可以看作是对VHL的改造！这也是基于对同类化合物共晶结构的了解，在VHL溶剂暴漏区进行的位点选择。筛选流程如下：研究人员设计了3个调节，筛选流程如同常规靶蛋白固载筛选流程。三个条件分别是双蛋白共孵育（仅靶蛋白固载）、不加呈递蛋白、不加靶蛋白和呈递蛋白。筛选后，数据展示出来的分别是三元复合物、和呈递比率的图示，如下。BRD9/VCB的富集化合物呈三组分布:(1)高富集和低呈现率，以连接器9(9系)和12(12系)的化合物为主;(2)中等三元富集和中等呈现比，以连接11(11系)的化合物为主;(3)低三元富集和高呈现物比，以连接13(13系)的化合物为主研究人员选择了16个化合物进行off-DNA重合成，如下表：研究发现，高呈递比率的化合物没有钩效应。如化合物9-1呈递比率较低（0.54），化合物13-7呈递比率高（34）。其中，化合物13-7针对BRD9和VCB具有最高的协同作用。而且，化合物13-7诱导更多的三元复合物，以及较少的二元复合物，在细胞中诱导的EC50 = 17 nM。这项研究对分子胶的合理设计和高通量发现具有非常重要的指导意义！此外，Stuart在2022年bioRxiv预刊上还发表了其针对PROTACs文库的高通量筛选，并于2024年正式刊载在顶级期刊Nature Chemical Biology上。方法类似，也是选择的VHL作为E3配体。接下来简要介绍 case 04.Case / 04BRDxby Broad Institute of MIT and HarvardPROTACs文库设计：也是基于已知的PROTAC分子与POI和E3连接酶共晶结构的了解，进行的DEL文库的设计，如下图。如下图是针对BRD4筛选后进行的数据分析和挑选出来的化合物进行重合成。这些化合物都具有个位数微摩尔级别和次微摩尔级别的三元结合能力和二元结合能力，并且两者之间比较接近。通过检测，邻近诱导物CIP1-4都有nM级别的抑制活性（19-38 nM）。此外，研究人员还对BRD2BD1 and BRDTBD1等靶点进行了筛选。因为是同家族靶标，研究人员观察到许多在BRD4BD1筛查中看到的相同趋势。例如，对于C15连接器和BB2-109/BB3-114，观察到同样强烈的偏好。Case / 05BRD4by HK University & SIMM今年2月份香港大学李笑宇教授联合上海药物所陆晓杰教授，在ChemRxiv预刊上也刊载了他们基于DEL发现可诱导蛋白降解的化合物的成果。研究人员采用的是基于POI泛素化的筛选方法，这是一种功能化的DEL筛选，而非POI结合或者形成三元复合物。因此鉴定的化合物在功能上更相关，更能预测活性蛋白质降解。DEL化合物文库的设计和筛选：如下图DEL化合物文库的构建设计：如上图A所示，研究人员这里将E3配体、POI配体、以及中间的连接子分别用DNA序列编码，三个组成部分类似于经典DEL文库合成中的分子砌块，这里通过双功能性连接子把三部分组合起来，并用DNA序列编码，包含950个组合成员。功能性筛选设计：在筛选中，文库与POI和E3连接酶复合物孵育，然后添加E1, E2, Ub和ATP(上图1B)。文库中潜在的PROTACs将使POI靠近蛋白复合物，也可能促进POI与E3连接酶之间的蛋白-蛋白相互作用，从而促进POI的多泛素化。接下来，串联泛素结合实体，将被用来捕获和分离含有富集化合物的泛素化三元配合物。富集的分子后续经过扩增、测序、分析鉴定等。研究人员同时设置了不加ATP，无法进行泛素化的对照组。DNA偶联嵌合体在细胞中的降解验证：研究人员首先验证了DNA偶联的嵌合体能否在细胞内诱导POI泛素化并降解，如下图。研究人员以BRD4、VHL为模型，合成了带有AOP-HP的嵌合体工具分子，转染进细胞内，进行降解验证。偶联物在2 μM时导致BRD4适度降解，还可以被蛋白酶体抑制剂carfilzomib所恢复，而与更多PEG单元(PTC-2、3和4)偶联物的活性很小。同时也发现连接体分支点的手性的对降解活性的影响至关重要。细胞实验的成果验证鼓舞着研究人员继续进行体外的泛素化实验测试，同样得到的证明。这表明，上面的筛选策略的设计是有效的！接下来，研究人员制备了一个模型库，继续进行验证，如下图。模型库包含活性降解剂PTC-5，三个非降解剂嵌合体PTC-2、PTC-3、和PTC-4（手性不同、链长不同），以及作为背景的DNA序列。通过这个模型库，针对BRD4-BD1进行体外验证，并设计了不添加ATP对照组。从上图B中的2D图中可以看出，潜在的苗头化合物具有较高的富集倍数、和筛选后序列数。从图C中也能清晰的看出，只有活性降解物PTC-5从筛选中被强烈富集！模型验证是成功的！理论得以验证，接下来，研究人员通过如下图的方案构建了一个950个分子的DEL文库。其中，选择了19个三官能团支架作为连接子、4个BRD4配体、以及10个VHL配体。通过筛选，分别在高浓度、低浓度环境下，富集出来比较明显的信号，并挑选了其中的分子进行重合成、验证，如下图。最终，通过这种方法，研究人员鉴定出了一种有效的BRD4-BD1降解剂（DC50: ~9.7 nM）和一种短型同源型选择性BRD4降解剂（DC50: 0.26 μM）。该报道从最初的设计理念、到一步步的概念验证、最终实现DEL文库的合成和高通量功能降解剂的筛选、鉴定，逻辑紧密，丝丝入扣，非常具有参考、指导意义！总结与展望：学术界和企业不懈的努力，推动技术的快速发展、和应用。以上介绍了DNA编码化合物库筛选技术，通过不同的方案，实现了对PROTACs、分子胶等蛋白靶向降解剂（TPD）的高通量、合理化设计、合成、筛选、鉴定。可以是高通量发现亲和力元件，再进行二度设计PROTACs分子，因为DEL分子本身和PROTACs分子的高度相似性；可以直接设计高通量PROTACs、分子胶文库，并针对靶标和E3连接酶进行筛选；也可以通过化合物库、筛选条件的设计，直接进行功能性设计、筛选，挑选出降解剂的；总有一款适合你。当前，也有报道基于DNA编码化合物库筛选为嵌合体核糖核酸酶（RiboTAC）的设计提供信息等，后续再聊（J Am Chem Soc， 2022, 144, 21096−21102）针对靶向降解剂的发现，欢迎留言交流！参考文献Selection of DNA-encoded Chemical Libraries for Compounds that can Induce Protein Ubiquitination. ChemRxiv, 2024, preprint(By Lu Xiaojie & Li Xiaoyu Group)DOI: 10.26434/chemrxiv-2024-rmgtvDNA-encoded library-enabled discovery of proximity-inducing small molecules. Nature Chemical Biology, 2024, 20, 170-179.(By Broad Institute of MIT and Harvard)DOI: 10.1038/s41589-023-01458-4Rational Screening for Cooperativity in Small-Molecule Inducers of Protein–Protein Associations. Journal of the American Chemical Society, 2023, 145(42), 23281-23291.(By Broad Institute of MIT and Harvard)DOI: 10.1021/jacs.3c08307Optimization of PROTAC Ternary Complex Using DNA Encoded Library Approach. ACS Chemical Biology, 2023,18(1), 25-33.(By HitGen)DOI: 10.1021/acschembio.2c00797Bispecific Estrogen Receptor α Degraders Incorporating Novel Binders Identified Using DNA-Encoded Chemical Library Screening. Journal of Medicinal Chemistry, 2021, 64(8), 5049-5066. (By X-Chem)DOI: 10.1021/acs.jmedchem.1c00127Molecular Glues & Bifunctional Compounds: Therapeutic Modalities Based on Induced Proximity. ChemRxiv, 2024, preprint(By Broad Institute of MIT and Harvard))DOI: 10.26434/chemrxiv-2024-q1n61-v2HitGen官网：DEL for 蛋白降解剂开发https://www.hitgen.com/cn/capabilities-details-120X-Chem官网：Targeted Protein Degradation & Molecular Glueshttps://www.x-chemrx.com/targeted-protein-degradation-molecular-glues/声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

蛋白降解靶向嵌合体

2023-09-12

·PRNewswire

Menopause Market to Grow Rapidly at a CAGR of 1.2% by 2032, Predicts DelveInsight

The menopause market is anticipated to surge significantly in the coming years due to the emergence of new products in the pipeline. In addition, persistently rising cases of menopause in the forecast period will help increase the menopause treatment market. LAS VEGAS, Sept. 12, 2023 /PRNewswire/ -- DelveInsight's Menopause Market Insights report includes a comprehensive understanding of current treatment practices, menopause emerging drugs, market share of individual therapies, and current and forecasted market size from 2019 to 2032, segmented into 7MM [the United States, the EU-4 (Italy, Spain, France, and Germany), the United Kingdom, and Japan]. Key Takeaways from the Menopause Market Report As per DelveInsight analysis, the menopause market size in the 7MM was approximately USD 11 billion in 2022. According to the assessment done by DelveInsight, the total number of women in menopause in the 7MM comprised approximately 100 million cases in 2022 and are projected to increase during the forecast period. Leading menopause companies such as Viramal Limited, Simbec Research, Estetra, Mithra Pharmaceuticals, Bayer, Nerre Therapeutics Ltd., Mitsubishi Tanabe Pharma America Inc., MenoGeniX, QUE Oncology, Fervent Pharmaceuticals, and others are developing novel menopause drugs that can be available in the menopause market in the coming years. The promising menopause therapies in the pipeline include Transdermal Estradiol Cream (VML-0203), DONESTA (E4, Estetrol), Elinzanetant (BAY3427080), MT-8554 (Elismetrep), MNGX-100 (Filgrastim/G-CSF), Q-122 (MSX-122), FP-101, and others. Discover which therapies are expected to grab the major menopause market share @ Menopause Market Report Menopause Overview Menopause is a natural biological process that marks the end of a woman's reproductive years. It usually occurs between the ages of 45 and 55, with an average age of around 51. This phase is characterized by a decline in the production of hormones like estrogen and progesterone, leading to the cessation of menstruation and fertility. The primary cause of menopause is the aging of the ovaries, which results in a reduced number of eggs and a decline in hormone production. However, certain medical procedures like hysterectomy, chemotherapy, and radiation therapy can induce menopause prematurely. Menopause brings about a range of symptoms that can vary widely from woman to woman. Common menopause symptoms include hot flashes, night sweats, mood swings, irritability, fatigue, vaginal dryness, and sleep disturbances. These symptoms occur due to the hormonal fluctuations that take place during the transition to menopause. Diagnosing menopause is often based on a woman's age, medical history, and symptoms. A key factor is the absence of menstruation for 12 consecutive months, signaling the end of the reproductive period. In some cases, healthcare providers may recommend blood tests to measure hormone levels, such as follicle-stimulating hormone (FSH) and estrogen, to confirm the onset of menopause. Menopause Epidemiology Segmentation DelveInsight estimates that there were approximately 100 million total women in menopause in the 7MM in 2022. For the age-specific analysis, the number of cases of menopause were distributed across various age groups, such as <40 years, 40–50 years, 51–60 years, and 61–65 years, in the 7MM. As per the analysis, the highest number of cases were estimated in the age-group 51-60 years and the lowest in <40 years with 64 million and 3.4 million cases, respectively in 2022. The menopause market report proffers epidemiological analysis for the study period 2019–2032 in the 7MM segmented into: Total Number of Women in Menopause Stage-Specific Distribution of Women in Menopause Age-Specific Distribution of Women in Menopause Number of Women in Menopause with Vasomotor Symptoms Number of Women in Menopause with Moderate-to-Severe Vasomotor Symptoms Menopause Treatment Market The North American Menopause Society (NAMS) suggests waiting until the hot flashes become troublesome to the woman before seeking treatment. The intensity of symptoms, an assessment of treatment-related risks, and the woman's views towards menopause and drugs should all be considered before starting treatment. Duavee (bazedoxifene acetate/conjugated estrogens) is the first and only medicine that combines CE with an estrogen agonist/antagonist, commonly known as a selective estrogen receptor modulator (SERM), for the treatment of menopausal VMS. Duavee employs bazedoxifene rather than progestin to help protect the uterine lining from hyperplasia that may occur as a result of estrogen-only treatment. Many women use non-prescription therapies to address disorders such as hot flashes, such as isoflavones, black cohosh, and progesterone-containing hormone lotions. The clinical evidence for the efficacy and long-term safety of these therapies is insufficient. Furthermore, most over-the-counter medications for hot flashes are classified as nutritional supplements and, as such, are not regulated by the US Food and Drug Administration. Prescription medications for various purposes that have demonstrated some benefit in alleviating hot flashes are available for women who have hot flashes but cannot undergo hormone therapy. Certain prescription antidepressants may reduce hot flashes in women, including those with a history of breast cancer. Others include gabapentin, clonidine, and methyldopa. The NAMS recommends that women who need relief from mild menopause-related hot flashes first consider lifestyle changes such as manipulating the environment to keep the core body temperature cool, getting regular exercise, quitting smoking, and using relaxation techniques such as paced respiration. To know more about menopause treatment, visit @ Menopause Treatment Drugs Key Menopause Therapies and Companies Transdermal Estradiol Cream (VML-0203): Viramal Limited/Simbec Research DONESTA (E4, Estetrol): Estetra/Mithra Pharmaceuticals Elinzanetant (BAY3427080): Bayer|Nerre Therapeutics Ltd. MT-8554 (Elismetrep): Mitsubishi Tanabe Pharma America Inc. MNGX-100 (Filgrastim/G-CSF): MenoGeniX Q-122 (MSX-122): QUE Oncology FP-101: Fervent Pharmaceuticals Learn more about the FDA-approved drugs for menopause @ Drugs for Menopause Treatment Menopause Market Dynamics The menopause market dynamics are undergoing significant shifts as societal awareness of women's health and well-being continues to grow. With an aging population and increasing focus on women's empowerment, there's a heightened demand for innovative products and services addressing the physical and emotional challenges associated with menopause. This has spurred a surge in research and development, leading to the creation of a diverse range of hormone replacement therapies, herbal supplements, lifestyle apps, and personalized health plans. As more women seek effective and holistic solutions, companies are embracing a more consumer-centric approach, tailoring their offerings to individual needs and preferences. Additionally, discussions around menopause are becoming less taboo, allowing for open dialogue and information-sharing, further shaping the menopause market dynamics by fostering a supportive ecosystem for women navigating this life stage. However, despite the potential for growth, this menopause market is not without its barriers. Stringent regulatory processes for hormonal treatments and supplements, coupled with concerns about product safety and efficacy, pose challenges for menopause market entrants. Additionally, cultural stigmas and misinformation surrounding menopause still exist in certain societies, inhibiting open discussions and the adoption of new solutions. Economic disparities and limited access to healthcare further compound these issues, preventing equal menopause market penetration. Overcoming these barriers requires a multi-faceted approach, involving education, regulatory reforms, and inclusive product development, to truly tap into the menopause market's potential. Scope of the Menopause Market Report Therapeutic Assessment: Menopause current marketed and emerging therapies Menopause Market Dynamics: Attribute Analysis of Emerging Menopause Drugs Competitive Intelligence Analysis: SWOT analysis and Market entry strategies Unmet Needs, KOL's Views, Analyst's Views, Menopause Market Access and Reimbursement Discover more about menopause drugs in development @ Menopause Clinical Trials Table of Contents Related Reports Hot Flashes Pipeline Hot Flashes Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key hot flashes companies, including Veru Healthcare, Fervent Pharmaceuticals, Ogeda, Bayer, Lundbeck A/S, TherapeuticsMD, MenoGeniX, Mitsubishi Tanabe Pharma, QUE Oncology, Pherin Pharmaceuticals, among others. Hot Flashes Market Hot Flashes Market Insight, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the market trends, market drivers, market barriers, and key hot flashes companies, including Veru Healthcare, Fervent Pharmaceuticals, Ogeda, Bayer, Lundbeck A/S, TherapeuticsMD, MenoGeniX, Mitsubishi Tanabe Pharma, QUE Oncology, among others. Menopause Global Market Menopause Market Insights, Competitive Landscape, and Market Forecast – 2028 report deliver an in-depth understanding of the disease, market trends, market drivers, market barriers, and key menopause companies including ISIDEN, Novapharm, Arkopharma, Pileje, Thermamex, ÉLERTÉ Laboratories, Serelys Pharma, Besins Healthcare, Bayer, ITALFARMACO S.p.A, Pfizer Inc, Mylan NV, Teva Pharmaceuticals, TherapeuticsMD, Inc, Novo Nordisk, Novartis, Millicent Pharma, PADAGIS LLC, Vertical Pharmaceuticals LLC, Amgen, among others. Vasomotor Symptoms of Menopause Pipeline Vasomotor Symptoms of Menopause Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key vasomotor symptoms of menopause companies, including Mithra Pharmaceuticals, Acer Therapeutics, QUE Oncology, Bayer, Endoceutics, Astellas Pharma, Mitsubishi Tanabe Pharma, MenoGenix, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +1(919)321-6187 Logo: SOURCE DelveInsight Business Research, LLP

2022-06-30

·药明康德

治疗不足现象突出！《自然》子刊综述：女性进入这个关键年龄段，如何合理应用激素治疗?

▎药明康德内容团队编辑绝大多数经历绝经期的女性都会面临令人烦恼的雌激素缺乏症状，绝经期雌激素水平的下降会引起女性身体无症状的生物学变化，并且增加非传染性疾病，如心血管疾病、2型糖尿病、骨质疏松、特定类型癌症以及抑郁症的发病风险。值得一提的是，提早绝经的女性这些疾病发生的风险更高。近日，《自然》子刊 Nature Reviews Endocrinology 发表重磅综述，围绕绝经的短期和远期影响、绝经相关症状治疗适应症以及绝经潜在治疗药物进行详细阐述。论文强调，对于有症状的绝经期女性，雌激素仍然是最有效的治疗方法。绝经激素疗法（MHT）不仅可以预防骨质流失以及骨折，如果在绝经期早期开始使用，还可用于预防心脏代谢疾病的发生。截图来源： Nature Reviews Endocrinology 绝经的短期和远期影响女性一生中需要经历很多个生理阶段，其中绝经期是女性从生育年龄过渡到老年的阶段。绝经后女性卵巢的功能基本消失，这一过程可能自然发生（自然绝经）或基于医源性因素发生（继发性闭经）。目前在全球范围内，女性自然绝经的平均年龄为48.8岁，不同地区女性自然绝经年龄差异较小。女性绝经年龄对晚年健康具有重要影响。提早绝经与乳腺癌的发病风险降低有关，但是会增加卵巢早衰相关骨质疏松、心血管疾病和过早死亡的风险。绝经雌激素水平的下降会诱导衰弱性症状的产生，如血管舒缩症状（如潮热、盗汗）、焦虑、抑郁、泌尿生殖道萎缩、性功能障碍。此外，绝经后雌激素的缺乏也可能带来长期不良反应，其中最值得关注的包括骨质流失（骨折风险增加）、中心性（腹型）肥胖（增加心血管疾病发病风险）、2型糖尿病（T2DM）以及部分类型癌症的发病风险增加。目前最常报告的绝经期症状包括血管舒缩症状、睡眠障碍、情绪变化、关节痛、肌痛、泌尿生殖道萎缩、认知功能改变和体重增加。论文强调，绝大多数女性在45岁至55岁之间绝经，其中高达75%会出现雌激素缺乏相关症状。尽管目前临床上拥有安全的激素与非激素治疗手段，但是绝大多数伴有绝经症状的女性并未接受有效的、基于充足证据的获批治疗方法。绝经人群需要接受治疗的指征论文强调，雌激素水平下降将导致全身脂肪组织的增加和重新分布（内脏脂肪的比例增高），从而提高绝经人群心血管疾病、2型糖尿病、乳腺癌、子宫癌和结直肠癌的发病风险。由于绝经相关主要症状以及后遗症主要由于卵巢雌激素分泌减少所致，因此，基于雌激素、雌激素样化合物的绝经激素治疗（MHT）有望改善绝经期症状，并同时预防绝经期相关骨质流失、心脏代谢不良变化。 ▲雌激素水平变化对心脏代谢影响的可能途径（图片来源：参考资料[1]）绝经激素治疗最初的适应症包括绝经期症状的治疗以及绝经后女性（具有较高骨折风险）骨质疏松的预防。目前绝经激素治疗的适应症主要为绝经期血管舒缩症状。论文强调，女性绝经症状受到个人健康、社会心理、经济环境等多方面因素的影响，因此需考虑配合其他手段进行综合护理，如优化生活方式（如提高膳食营养、体能锻炼水平，减少饮酒和戒烟）、治疗慢性疾病相关的风险因素。绝经人群的治疗选择论文强调，绝经激素治疗（如使用药物替勃龙）是目前绝经相关症状最有效的治疗手段。在骨密度正常、骨量减少和骨质疏松的女性中，研究证实绝经激素治疗可显著降低受试者髋关节、椎体和其他骨质疏松相关骨折的风险。此外，对于常见的绝经相关泌尿生殖道萎缩，激素治疗结合非激素治疗手段也可为这部分人群带来积极获益。目前获批的绝经人群全身性激素治疗药物包括：雌激素类：结合型孕马雌激素（CEE）、微粉化17-β雌二醇、戊酸雌二醇、雌酮硫酸酯哌嗪、17-β雌二醇经皮吸收制剂、皮下埋植雌二醇、雌二醇凝胶、雌二醇半水合物凝胶；孕激素类：微粉化黄体酮、地屈孕酮、屈螺酮、醋酸炔诺酮、醋酸甲羟孕酮、左炔诺孕酮宫内节育系统；其他类型：替勃龙、共轭雌激素/巴多昔芬。对于不同类型的绝经人群，绝经激素治疗方案不同，具体而言对于接受子宫切除术的女性，应仅以最低有效剂量处方雌激素；对于保留子宫的女性，考虑到长期使用单一雌激素疗法可能会增加子宫内膜增生的发生风险，因此推荐雌激素治疗需与孕激素联合使用。此外，绝经期症状的非激素干预措施包括生活方式和饮食调整、非激素类药物、行为和替代疗法。但是，目前尚缺乏令人信服的证据证实，运动、营养补充剂或富含植物雌激素的饮食可有效缓解绝经相关症状，如血管舒缩症状。不过，越来越多的临床试验和荟萃分析的证据显示，特定抗抑郁药，如文拉法辛、帕罗西汀等，或可有效缓解绝经期血管舒缩症状。论文也强调，认知行为治疗有助于减少血管舒缩症状带来的影响，并可能对绝经期人群睡眠和情绪有额外益处。相关阅读《柳叶刀》子刊：乳腺癌5年复发风险进一步降低约32%，芳香化酶抑制剂对绝经前患者同样有效！《柳叶刀》专题：影响女性1/3生命，这个关键时期要保护心脏代谢健康为什么女性更多得甲状腺疾病？ JAMA 详述女性一生中的生理变化影响参考资料 [1] Davis, S.R., Baber, R.J. Treating menopause — MHT and beyond. Nat Rev Endocrinol (2022). https://doi.org/10.1038/s41574-022-00685-4 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：本文来自药明康德内容团队，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载至其他平台。转载授权请在「医学新视点」微信公众号留言联系。如有其他合作需求，请联系wuxi_media@wuxiapptec.com

合作

100 项与醋酸巴多昔芬相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	醋酸巴多昔芬	G03XC02	DB06401

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
绝经期后骨质疏松	欧盟	Pfizer Europe MA EEIG	2009-04-17
绝经期后骨质疏松	冰岛	Pfizer Europe MA EEIG	2009-04-17
绝经期后骨质疏松	列支敦士登	Pfizer Europe MA EEIG	2009-04-17
绝经期后骨质疏松	挪威	Pfizer Europe MA EEIG	2009-04-17

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
子宫内膜增生	临床3期	美国	Pfizer Inc.	2009-01-01
子宫内膜增生	临床3期	阿根廷	Pfizer Inc.	2009-01-01
子宫内膜增生	临床3期	澳大利亚	Pfizer Inc.	2009-01-01
子宫内膜增生	临床3期	智利	Pfizer Inc.	2009-01-01
子宫内膜增生	临床3期	哥伦比亚	Pfizer Inc.	2009-01-01
子宫内膜增生	临床3期	丹麦	Pfizer Inc.	2009-01-01
子宫内膜增生	临床3期	芬兰	Pfizer Inc.	2009-01-01
子宫内膜增生	临床3期	匈牙利	Pfizer Inc.	2009-01-01
子宫内膜增生	临床3期	墨西哥	Pfizer Inc.	2009-01-01
子宫内膜增生	临床3期	新西兰	Pfizer Inc.	2009-01-01

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


AACR2023	N/A	乳腺癌	21	Bazedoxifene 20 mg + Conjugated estrogen 0.45 mg	鬱製廠鹹積衊鹹醖襯觸(憲鬱觸觸膚襯鹽遞繭糧) = 繭鬱衊蓋窪淵糧願積遞鏇構築獵糧鏇糧蓋繭餘 (顧願鬱鏇夢製簾齋願憲 )	-	2023-04-04
				bazedoxifene (Wait list control)	鬱製廠鹹積衊鹹醖襯觸(憲鬱觸觸膚襯鹽遞繭糧) = 簾獵願鹹選餘衊鑰淵鹹鏇構築獵糧鏇糧蓋繭餘 (顧願鬱鏇夢製簾齋願憲 )
NCT02448771 (Pubmed)	临床2期	HR阳性乳腺癌	36	Bazedoxifene plus Palbociclib	醖選選醖窪構鬱鏇夢繭(廠窪繭鏇膚鏇鏇觸襯憲) = 膚齋鏇築膚鑰鏇壓網範壓願襯憲鑰憲壓觸鏇構 (遞鑰膚蓋膚餘製鹽選蓋 ) 更多	积极	2022-10-10
NCT02448771 (CTgov)	临床1/2期	HR阳性乳腺癌 \| 转移性乳腺癌 \| 浸润性乳腺癌	36	Bazedoxifene+palbociclib	糧艱鹽繭網醖蓋襯襯淵(鏇繭鹽窪簾鬱齋齋構鑰) = 顧壓積齋願積糧獵廠膚選顧鹹膚獵淵製鏇醖鹹 (簾願顧糧鏇願鬱鹹艱齋, 鬱簾壓膚糧鬱蓋構顧鏇 ~ 選壓觸遞獵鹹餘壓鑰積) 更多	-	2021-07-01
NCT00808132 (Selective estrogens, Menopause, And Response to Therapy-5, CTgov)	临床3期	子宫内膜增生 \| 绝经期后骨质疏松	1,886	Bazedoxifene (Bazedoxifene 20 mg / Conjugated Estrogens 0.45 mg)	鹽廠網選壓鑰窪鑰製衊(鹹齋鑰糧醖鹽窪壓壓繭) = 衊鹽糧餘繭繭獵餘網艱鑰獵鑰鬱繭憲願憲壓艱 (構簾積壓顧鑰顧構選鏇, 鏇窪鬱顧衊醖繭窪選網 ~ 艱繭築繭簾顧遞艱鬱衊) 更多	-	2013-12-20
				Bazedoxifene (Bazedoxifene 20 mg / Conjugated Estrogens 0.625 mg)	鹽廠網選壓鑰窪鑰製衊(鹹齋鑰糧醖鹽窪壓壓繭) = 繭獵觸鏇衊顧憲選醖蓋鑰獵鑰鬱繭憲願憲壓艱 (構簾積壓顧鑰顧構選鏇, 襯顧觸襯製夢衊觸簾鏇 ~ 積壓壓遞鹽餘顧糧餘鏇) 更多
NCT00205777 (CTgov)	临床3期	骨质疏松症 \| 骨折	7,609	Bazedoxifene (Bazedoxifene 20 mg (Core+SE I))	選鹹廠壓鹽壓觸襯遞醖(夢憲窪鹽齋蓋糧選鏇醖) = 蓋憲鑰網構構選襯艱糧顧蓋膚構糧積顧製餘憲 (膚鏇鹹繭範壓積遞廠願, 範窪顧衊衊範衊鹽繭鹽 ~ 製顧鹽構鬱積齋艱襯網) 更多	-	2013-04-10
				Bazedoxifene (Bazedoxifene 40 mg (Core))	選鹹廠壓鹽壓觸襯遞醖(夢憲窪鹽齋蓋糧選鏇醖) = 壓鹹選繭襯廠選襯鏇積顧蓋膚構糧積顧製餘憲 (膚鏇鹹繭範壓積遞廠願, 鑰膚艱廠蓋願選鑰廠遞 ~ 鹹醖襯範糧繭衊觸網積) 更多
NCT00238745 (Pubmed \| N Engl J Med)	临床2期	绝经期后骨质疏松	429	Bazedoxifene 20 mg	壓淵襯築範繭鏇簾構鬱(鬱壓鏇齋鏇壓選顧遞構) = 餘顧鹹鑰衊膚鬱鑰糧遞顧獵範憲夢製窪醖艱鹹 (齋遞製鹽衊艱願網鹹築 )	-	2011-03-01
				Bazedoxifene 40 mg	壓淵襯築範繭鏇簾構鬱(鬱壓鏇齋鏇壓選顧遞構) = 製繭構觸艱廠構構窪製顧獵範憲夢製窪醖艱鹹 (齋遞製鹽衊艱願網鹹築 )