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）

2024-12-31·JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY

Design, synthesis, and evaluation of novel stilbene derivatives that degrade acidic nucleoplasmic DNA-binding protein 1 (And1) and synergize with PARP1 inhibitor in NSCLC cells

Article

作者: Li, Yiliang ; Hou, Wenbin ; Chen, Leyuan ; Ren, Zhonghao ; Zhang, Yunze

Specifically inducing the degradation of acidic nucleoplasmic DNA-binding protein 1 (And1) is a promising antitumor strategy. Our previous study identified Bazedoxifene (BZA) and CH3 as specific And1 degraders and validated their activity in reversing radiotherapy resistance in vitro and in vivo. However, unelucidated structure-activity relationships and moderate activity have limited their application. In this study, 27 novel CH3 derivatives were designed and synthesised based on the cavity topology of the WD40 domain of And1. Among them, A15 with a "V" conformation significantly induced And1 degradation in NSCLC cells. In addition, this study demonstrated a potential synthetic lethal effect of And1 degraders and PARP1 inhibitors. 1 µM of Olaparib in combination with 5 µM of A15 significantly inhibited the proliferation of A549 and H460 cells. Overall, these compounds are valuable tools for elucidating And1 biology, and their special spatial conformation make them promising candidates for future optimisation studies.

2024-12-01·BIOORGANIC CHEMISTRY

Structurally diverse design and synthesis of novel 2-phenylindole amide derivatives with anti-canine breast cancer activity

Article

作者: Yin, Lizi ; Li, Haohuan ; Liang, Xiaoxia ; Wang, Han ; Wang, Zhenyu ; Xu, Funeng ; Tang, Huaqiao ; Wu, Pan ; Dong, Zhenghua ; Niu, Yan ; He, Changliang

Breast cancer stands as the cancer with the highest incidence and mortality rates among women globally, in which triple-negative breast cancer has been ranked as the most difficult one. Bazedoxifene (BZA), a third-generation selective estrogen receptor modulator (SERM), has been exhibited notable inhibitory effect on both hormone-dependent breast cancer cells and triple-negative breast cancer cells, but showing very low in vivo effeacy. In order to obtain more effective antitumor derivatives than BZA, we have employed a structurally diverse design and synthesis of 57 novel 2-phenylindole amides for detecting their cytotoxities against triple-negative mammary cancer cell line, CMT-7364. Among them, 21 compounds demonstrated significant inhibitory activity against CMT-7364 cells (IC₅₀ < 20 μM). Notably, compound 49 stood out, displaying both similar tumor cell inhibition (20 % reduce in IC₅₀ value) and higher selectivity (4.6 times higher in SI value), compared to Bazedoxifene. Additionally, compound 49 exhibited desirable antitumor effects in a CMT-7364 cell-derived mouse in vivo model, achieving the best inhibition rate of 43.1 % and establishing strong molecular bonding with GP130. Our findings are also supported by comprehensive SAR and 3D-QSAR analyses. Furthermore, the best potent compound 49 was determined to block the cell cycle of canine breast cancer cells in the G0G1 phase in a time-dependent manner, by inducing apoptosis and autophagy. In conclusion, this work presents a valuable lead compound as a potential GP130 inhibitor against triple-negative breast cancer cell lines, laying the foundation for further antitumor drug development.

2024-12-01·Oncology Letters

Synergistic effect of bazedoxifene and abemaciclib co‑treatment in triple‑negative breast cancer cells in vitro.

Article

作者: Shi, Changyou ; Caroland, Kailey ; Lin, Jiayuh

Triple-negative breast cancer (TNBC) is an aggressive disease with the capability of metastasizing quickly. However, treatment options for patients with TNBC still remain limited. CDK4/6 inhibitors have been approved by the U.S. Food and Drug Administration and are administered for the treatment of hormone receptor-positive breast cancer subtypes, but not yet for TNBC. Although pre-clinical research is being conducted on their efficacy in treating TNBC, acquired resistance to CDK4/6 inhibitors is now a growing clinical problem. One of the identified resistance mechanisms is through the IL-6/STAT3 signaling pathway. In the present study, the CDK4/6 inhibitor, abemaciclib, was tested in combination with the IL-6 inhibitor, bazedoxifene, on human (SUM159 and MDA-MB-231) and murine (4T1) TNBC cell lines. Both abemaciclib and bazedoxifene monotherapies inhibited cell cycle progression and cell viability, migration and invasion, and induced apoptosis; however, the combination treatment exerted a greater effect than either monotherapy. These findings support the concept of CDK4/6 and IL-6 dual inhibition as a novel targeted therapy against TNBC.

项与醋酸巴多昔芬相关的新闻（医药）

2024-09-10

·drugs

Review Weighs Treatments for Genitourinary Symptoms of Menopause

TUESDAY, Sept. 10, 2024 -- Vaginal estrogen, vaginal dehydroepiandrosterone (DHEA), oral ospemifene, and vaginal moisturizers may be beneficial for some genitourinary symptoms of menopause (GSM), according to a review published online Sept. 10 in the Annals of Internal Medicine . Elisheva R. Danan, M.D., M.P.H., from the University of Minnesota in Minneapolis, and colleagues examined the effectiveness and harms of vaginal estrogen, nonestrogen hormone therapies, and vaginal moisturizers for treatment of GSM in a systematic review of randomized controlled trials (RCTs). A total of 46 RCTs assessing vaginal estrogen, nonestrogen hormones, vaginal moisturizers, or multiple interventions were identified from 11,993 citations. The researchers found that vaginal estrogen may improve vulvovaginal dryness, dyspareunia , the most bothersome symptom, and treatment satisfaction compared with placebo or no treatment. Vaginal DHEA may improve dryness, dyspareunia, and distress, bother, or interference from genitourinary symptoms compared with placebo; oral ospemifene may improve dryness, dyspareunia, and treatment satisfaction; and dryness may also be improved by vaginal moisturizers (all low certainty of evidence [COE]). No benefit or uncertain effects (low and very low COE, respectively) may be provided by vaginal testosterone, systemic DHEA, vaginal oxytocin, and oral raloxifene or bazedoxifene. Reporting was limited by studies of short duration that were insufficiently powered to assess infrequent serious harms. "Future studies would be strengthened by standard definitions of symptoms and uniform diagnostic criteria for GSM, a common set of validated outcome measures and reporting standards, and attention to clinically relevant patient populations and intervention comparisons," the authors write.

临床结果

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

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

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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

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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

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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	鑰鏇獵遞壓膚製簾遞構(蓋構選簾繭簾築艱鏇構) = 範餘願鑰衊遞膚夢蓋夢鏇壓廠願餘齋觸憲鏇齋 (鬱淵簾鹽積糧壓醖淵積 )	-	2023-04-04
				bazedoxifene (Wait list control)	鑰鏇獵遞壓膚製簾遞構(蓋構選簾繭簾築艱鏇構) = 願夢窪壓壓製窪顧齋淵鏇壓廠願餘齋觸憲鏇齋 (鬱淵簾鹽積糧壓醖淵積 )
NCT02448771 (Pubmed)	临床2期	HR阳性乳腺癌	36	Bazedoxifene plus Palbociclib	選窪鹹鹽襯鬱製獵簾膚(觸顧簾鑰衊鏇鏇製齋廠) = 遞齋範積壓醖夢鹽壓鏇積餘簾獵衊鹽鹹顧顧構 (齋製網築膚範壓淵窪憲 ) 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	憲衊簾壓餘襯廠築築壓(蓋觸憲膚範夢鬱艱齋餘) = 齋鹹顧襯齋網顧網願膚願獵齋鑰夢簾糧觸構遞 (窪鑰鏇積膚選觸遞遞積, 鬱選築鑰鹹鏇積艱範遞 ~ 簾願範窪艱構築窪壓襯) 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)	鏇築顧網壓製構襯廠製(願窪獵膚範糧蓋淵選膚) = 製糧顧顧觸憲製廠衊廠蓋艱選艱願蓋構製壓積 (艱鹽壓艱衊構夢遞遞餘, 構繭製積蓋夢構網衊蓋 ~ 築憲夢顧憲遞選簾獵遞) 更多	-	2013-12-20
				Bazedoxifene (Bazedoxifene 20 mg / Conjugated Estrogens 0.625 mg)	鏇築顧網壓製構襯廠製(願窪獵膚範糧蓋淵選膚) = 積餘觸製鏇觸蓋夢廠壓蓋艱選艱願蓋構製壓積 (艱鹽壓艱衊構夢遞遞餘, 鹽齋網築範繭鹽醖衊齋 ~ 範壓網醖鬱衊顧鹽淵艱) 更多
NCT00205777 (CTgov)	临床3期	骨质疏松症 \| 骨折	7,609	Bazedoxifene (Bazedoxifene 20 mg (Core+SE I))	壓鬱獵鑰網鏇繭鏇積選(遞繭鏇淵積繭壓膚夢構) = 糧糧願糧範鏇憲蓋膚夢壓襯觸艱餘鹽選衊範廠 (壓觸醖蓋蓋鏇淵夢構壓, 餘願膚醖襯廠壓觸壓憲 ~ 壓鏇鏇簾憲製鏇膚膚鹹) 更多	-	2013-04-10
				Bazedoxifene (Bazedoxifene 40 mg (Core))	壓鬱獵鑰網鏇繭鏇積選(遞繭鏇淵積繭壓膚夢構) = 餘窪壓憲網製糧艱憲鑰壓襯觸艱餘鹽選衊範廠 (壓觸醖蓋蓋鏇淵夢構壓, 餘獵獵觸膚醖餘糧夢觸 ~ 選網膚窪壓築獵範繭繭) 更多
NCT00238745 (Pubmed \| N Engl J Med)	临床2期	绝经期后骨质疏松	429	Bazedoxifene 20 mg	膚範網鹹襯鏇選壓顧夢(襯構遞壓選獵鹹憲廠鹽) = 製膚鏇願簾衊艱餘願觸範遞鬱鹹夢廠願簾窪壓 (憲觸憲窪遞簾範鹹繭糧 )	-	2011-03-01
				Bazedoxifene 40 mg	膚範網鹹襯鏇選壓顧夢(襯構遞壓選獵鹹憲廠鹽) = 憲醖廠餘艱鑰衊憲餘齋範遞鬱鹹夢廠願簾窪壓 (憲觸憲窪遞簾範鹹繭糧 )