This phase I trial studies the side effects and best dose of GSK525762C (molibresib besylate) and entinostat in treating patients with solid tumors or lymphomas that have spread to other parts of the body (advanced) or are not responding to treatment (refractory). GSK525762C and entinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. This study may help doctors find out if giving the combination of GSK525762C and entinostat is better or worse than the usual approach for treating solid tumors or lymphomas.

开始日期2020-09-18

申办/合作机构

National Cancer Institute

NCT04116359

/ Withdrawn临床1/2期IIT

A Phase 1/2 Study of the Bromodomain Inhibitor Molibresib in Combination With Etoposide/Platinum in Patients With NUT Carcinoma

This phase I/II trial studies the side effects and best dose of molibresib when given together with chemotherapy (etoposide and cisplatin) and how well they work for the treatment of NUT cancer that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Molibresib may stop the growth of tumor cells by blocking some of the proteins needed for cell growth. Drugs used in chemotherapy, such as etoposide and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding molibresib to chemotherapy (etoposide and cisplatin), may work better in treating patients with NUT cancer compared to the usual approach.

开始日期2020-09-18

申办/合作机构

National Cancer Institute

NCT02964507

/ Terminated临床1期

A Phase I/II Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK525762 in Combination With Fulvestrant in Subjects With Hormone Receptor-positive/HER2-negative (HR+/HER2-) Advanced or Metastatic Breast Cancer

This is a combination Phase I and Phase II study, with an aim to evaluate the combination of GSK525762 and fulvestrant in women with HR+/HER2- advanced or metastatic breast cancer, who have disease that has progressed after prior treatment with at least one line of endocrine therapy. The objectives of the study are to first identify, in open-label single-arm Phase I, a recommended Phase II dose of GSK525762 that may be combined safely with fulvestrant. Phase I will follow a modified toxicity probability interval (mTPI) design, and a sentinel group will be evaluated first for dose-limiting toxicity and further expanded to collect additional safety data. This will be followed by a double-blind, randomized controlled Phase II, to identify the clinical activity of the two study treatments when given in combination. The composition of Phase II will be selected at the end of Phase I.

开始日期2019-09-26

申办/合作机构

GSK Plc

100 项与 Molibresib 相关的临床结果

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100 项与 Molibresib 相关的转化医学

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100 项与 Molibresib 相关的专利（医药）

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253

项与 Molibresib 相关的文献（医药）

2025-03-01·VIROLOGY

A high-throughput, microplate reader-based method to monitor in vitro HIV latency reversal in the absence of flow cytometry

Article

作者: Nkwelle, Chantal Emade ; Esemu, Seraphine N ; Ndip, Roland N ; Liang, Kimberly ; Ntie-Kang, Fidele ; Tietjen, Ian ; Cassel, Joel ; Stephens, Unique ; Salvino, Joseph M ; Montaner, Luis J

J-Lat cells are derivatives of the Jurkat CD4⁺ T cell line that contain a non-infectious, inducible HIV provirus with a GFP tag. While these cells have substantially advanced our understanding of HIV latency, their use by many laboratories in low and middle-income countries is restricted by limited access to flow cytometry. To overcome this barrier, we describe a modified J-Lat assay using a standard microplate reader that detects HIV-GFP expression following treatment with latency-reversing agents (LRAs). We show that HIV reactivation by control LRAs like prostratin and romidepsin is readily detected with dose dependence and with significant correlation and sensitivity to standard flow cytometry. For example, 10 μM prostratin induced a 20.1 ± 3.3-fold increase in GFP fluorescence in the microplate reader assay, which corresponded to 64.2 ± 5.0% GFP-positive cells detected by flow cytometery. Similarly, 0.3 μM prostratin induced a 1.7 ± 1.2-fold increase compared to 8.7 ± 5.7% GFP-positive cells detected. Using this method, we screen 79 epigenetic modifiers and identify CUDC-101, molibresib, and quisinostat as novel LRAs. This microplate reader-based method offers accessibility to researchers in resource-limited regions to work with J-Lat cells and more actively participate in global HIV cure research efforts.

2025-01-01·NATURE STRUCTURAL & MOLECULAR BIOLOGY

Resistance of estrogen receptor function to BET bromodomain inhibition is mediated by transcriptional coactivator cooperativity

Article

作者: Zhang, Sicong ; Roeder, Robert G ; Roeder, Robert G.

The bromodomain and extraterminal domain (BET) family of proteins are critical chromatin readers that bind to acetylated histones through their bromodomains to activate transcription. Here, we reveal that bromodomain inhibition fails to repress oncogenic targets of estrogen receptor because of an intrinsic transcriptional mechanism. While bromodomains are necessary for the transcription of many genes, bromodomain-containing protein 4 (BRD4) binds to estrogen receptor binding sites and activates transcription of critical oncogenes such as MYC, independently of its bromodomains. BRD4 associates with the Mediator complex and disruption of Mediator reduces BRD4's enhancer occupancy. Profiling changes of the post-initiation RNA polymerase II (Pol II)-associated factors revealed that BET proteins regulate interactions between Pol II and elongation factors SPT5, SPT6 and the polymerase-associated factor 1 complex, which associate with BET proteins independently of their bromodomains and mediate their transcription elongation effect. Our findings highlight the importance of bromodomain-independent functions and interactions of BET proteins in the development of future therapeutic strategies.

2024-09-15·Aging-US

RPL22L1 is a novel biomarker for prognosis and immune infiltration in lung adenocarcinoma, promoting the growth and metastasis of LUAD cells by inhibiting the MDM2/P53 signaling pathway

Article

作者: Zhao, Qi ; Xing, Shigui ; Li, Dongbing

The ribosomal protein L22-like1 (RPL22L1) is a constituent of the 60 S ribosomal subunit whose function in lung adenocarcinoma (LUAD) remains ambiguous. This study aims to elucidate the role of RPL22L1 in LUAD through a thorough analysis and experimental validation. Our findings indicate that RPL22L1 exhibits abnormal expression patterns in various cancer types, including LUAD. Moreover, a statistically significant association was observed between elevated levels of RPL22L1 expression in LUAD patients and several clinical parameters, such as pathological stage (p = 0.0083) and gender (p = 0.0038). The high expression of RPL22L1 in LUAD demonstrated a significant association with poorer overall survival (OS) (p = 0.005), progression-free survival (PFS) (p = 0.027), and disease-specific survival (p = 0.015). The expression of RPL22L1 in LUAD (p = 0.005) was identified as an independent prognostic factor. Additionally, RPL22L1 expression in LUAD was found to be correlated with immune infiltration, immune checkpoint genes, TMB/MSI, and mRNAsi. Notably, the expression of RPL22L1 exhibited significant negative correlations with 1-BET-762, Trametinib, and WZ3105 in LUAD. The RPL22L1 gene exhibited up-regulation in multiple individual cells of LUAD, leading to a comparatively shorter PFS in the RPL22L1 variant group as opposed to the RPL22L1 variant-free group in LUAD. Significantly increased expression of RPL22L1 was noted in LUAD cell lines, where it was found to enhance the growth and metastasis of LUAD cells by suppressing the MDM2/P53 signaling pathway. Therefore, RPL22L1 may serve as a promising prognostic biomarker and therapeutic target for patients with LUAD.

项与 Molibresib 相关的新闻（医药）

2023-03-14

·CPHI制药在线

关注 | 裁员17%，管线砍掉大半，这家德国药企的“保留项目”有何看点？

关注并星标CPHI制药在线近日，德国慕尼黑MorphoSys AG宣布计划停止所有临床前管线，并裁减17%的员工，以延长其现金跑道，届时MorphoSys将有110名员工失业。公司表示，后续将其主要资源集中于3款抗肿瘤药物。这三款仅存的产品分别是已上市的CD19抗体tafasitamab，在研产品BET抑制剂pelabresib及EZH2抑制剂CPI-0209。 CD19抗体tafasitamab Tafasitamab是一款靶向CD19的人源化单克隆抗体，也是目前MorphoSys AG唯一商业化上市的产品。2020年8月，FDA加速批准Tafasitamab上市，用来与来那度胺联用二线治疗成人复发或难治性（r/r）弥漫性大B细胞淋巴瘤（DLBCL）。2021年6月，欧洲药品管理局CHMP发表了积极意见，建议有条件批准tafasitamab和来那度胺联合治疗及后续tafasitamab单药治疗，用于不符合自体干细胞移植（ASCT）条件的r/r DLBCL成人患者的治疗。 Tafasitamab在开发过程中，使用Xmab技术平台，对抗体的Fc段进行改造，通过改造抗体的Fc端，能够将抗体与Fcγ受体的亲和力提高数十倍，从而更好地激活NK细胞、巨噬细胞等免疫细胞。临床数据表明，在使用来那度胺和Tafasitamab联合治疗r/r DLBCL成人患者中，试验数据显示：客观缓解率（ORR）为55%，完全缓解率（CR）为37％，部分缓解率（PR）为18％；中位缓解持续时间（mDOR）为21.7个月。最常见的不良反应是中性粒细胞减少。看到CD19这个靶点以及DLBCL，就会联想到CD19-CAR-T。虽然Tafasitamab临床效果稍逊一筹，但Tafasitamab的安全性更好，目前上市的CAR-T具有免疫相关不良反应，严重者甚至收到FDA的黑框警告，而Tafasitamab相关的不良反应主要为中性粒细胞减少。另外，目前上市的CAR-T产品多为自体来源，耗时长且价格昂贵，Tafasitamab则是一种工业化生产的即用型产品。 BET抑制剂pelabresib Pelabresib是一款潜在FIC的BET抑制剂，其用于治疗骨髓纤维化的III期MANIFEST-2研究正在进行中，将于明年初公布关键数据。 BET（溴结构域和超末端结构域）属于BD（溴结构域）大家族的一员，BD是一类由约110个氨基酸组成的、能够特异性识别组蛋白中乙酰化赖氨酸（KAc）的高度保守的蛋白结构域，其包含八大家族，其中BET是被研究较多的一个家族。 BET蛋白家族包含四个异构体，分别是：BRD2、BRD3、BRD4和BRDT。每个家族成员含有两个溴结构域（BD1、BD2）和一个超末端结构域（ET）。其中BD1和BD2识别并结合KAc从而发挥生理作用，ET结构域与辅助因子相互作用。BET家族蛋白通过BD1、BD2与乙酰化的染色质结合，从而在表观遗传学水平上对基因表达进行调控，广泛参与细胞周期、细胞分化、信号转导等过程，在许多肿瘤的发生、发展中起着重要作用。目前，一系列BET抑制剂正在研发中，不过BET抑制剂的研发极具挑战。这是因为BD1和BD2具有高度同源性，之前报道的大多BET抑制剂对BD1和BD2具有相似的亲和活性，这类抑制剂通常被称为泛BET抑制剂，如二氮杂及其衍生物（JQ1、IBET762、OTX015）等。这类抑制剂不但具有剂量限制性毒性而且其抗肿瘤活性比临床前观察到的弱。为了解决这些问题，开发高亚型选择性的BET抑制剂是未来的研发方向，这些高亚型选择性抑制剂包括BD1、BD2以及BRD4选择性抑制剂等。 Pelabresib就是在泛BET抑制剂JQ1的基础上进行优化改造而得。化合物JQ1是一种研发较早的BET小分子抑制剂，其作用疾病范围广泛，但是半衰期短且治疗过程中毒性较大，为了得到药效持久且毒性较低的高选择性BET抑制剂，Pelabresib在JQ1的基础上，用苯环替换代谢不稳定的噻吩环改造而来，它对BD1的抑制活性是BD2的6倍以上。在治疗骨髓纤维化患者的II期临床试验中，Pelabresib表现出积极的疗效，其与JAK抑制剂ruxolitinib联用，在未接受过JAK抑制剂治疗的患者中能够让67%的患者脾脏体积缩小35%以上。目前全球III期临床研究正在进行中。目前，多款高选择性BET抑制剂正在研发中。如GSK的BD1选择性抑制剂GSK779、艾伯维的BD2选择性抑制剂ABBV-744、以及靶向BRD4的PROTACs等。在国内，也有多家企业在进行相关产品的研发，如贝达药业的BET抑制剂BPI-23314，其能抑制BET相关多种癌症基因表达及降解靶蛋白BRD4等；文达医药的NHWD-870 HCl，是一款靶向BRD4的选择性抑制剂，拟开发用于治疗晚期复发非霍奇金淋巴瘤、非小细胞肺癌和小细胞肺癌等；加科思的BET抑制剂JAB-8263，临床前研究表明其对多种实体瘤和血液瘤均能发挥抗肿瘤作用。总之，BET抑制剂赛道已变得非常拥挤，不过以上BET抑制剂大多处于临床早期阶段。MorphoSys AG的Pelabresib是为数不多进入临床III期的高选择性BET抑制剂，未来有望率先撞线，是一款潜在FIC的骨髓纤维化疗法。 EZH2抑制剂CPI-0209 EZH2是一种组蛋白赖氨酸甲基转移酶，其通过催化组蛋白H3赖氨酸27（H3K27）的甲基化以控制各种基因表达，从而调节细胞的正常生理功能。在多种癌症中均存在EZH2的失调，另外EZH2的表达还与临床的不良预后和疗效相关。自EZH2在临床上发现其与肿瘤的发生及预后相关后，科学家们就尝试利用EZH2抑制剂来干预肿瘤发生的甲基化水平。2012年开始，Epizyme、诺华、GSK、辉瑞、第一三共等陆续入局EZH2抑制剂的研发。 MorphoSys AG的CPI-0209是一款新一代EZH2抑制剂，临床前研究显示，CPI-0209具有比其他EZH2抑制剂强10-500倍的效力，目前，它正在开展I/II期临床试验，治疗多种血液瘤和实体瘤患者。目前，大多EZH2抑制剂仍处于临床开发的前期，很多临床试验正在摸索中前进，尚未形成同质化恶性竞争，MorphoSys AG的CPI-0209尚有突围机会。上述三款产品是目前MorphoSys AG仅剩的三款产品，从分析可知，三款产品各有优势，且在研产品在领域内研发进度均靠前，未来很有希望分到市场的一杯羹。事实上，在资本寒冬下，缩减管线，及时调整研发策略是再正常不过的一件事，就连大厂也在不断瘦身，如辉瑞在2022年财报披露中曾透露，公司将剔除8个研发项目；BMS也在2022年财报中表示将削减9项资产；国内三叶草生物也在去年年中对外宣布，将优先把所有资源配置给新冠疫苗这一管线，减少非新冠项目的投入。如今，MorphoSys AG由于市场变化，欲将有限的资源集中到更具希望的临床后期管线项目上，虽然砍掉临床前团队这一决策的影响要在多年后才会得到验证，但就当下来说，这一决策不失为明智之举。毕竟，在资本寒冬下，如何活下去，活得好，才是当下创新biotech要思考的第一要义。参考来源： 1. https://www.morphosys.com/media-investors/media-center/fda-approves-monjuvir-tafasitamab-cxix-in-combination-with-lenalidomide; 2. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study [published online ahead of print, 2020 Jun 5]. Lancet Oncol. 2020;S1470-2045(20)30225-4. doi:10.1016/S1470-2045(20)30225-4; 3. Pan Tang,Jifa Zhang et al.（2021）. Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development.Journal of Medicinal Chemistry,DOI: 10.1021/acs.jmedchem.0c01487； 4. 陈金晶，赵晓丽等.（2017）.含溴结构域和额外终端域家族蛋白--表观遗传领域的新型治疗靶点。《药学学报》DOI：：10.16438/j.05l3-4870.2017-0143； 5. 宫玉芳等. 新兴抗肿瘤靶点EZH2作用机制及研究进展.《现代肿瘤医学》，2020, 28（10）, 1757-1760. 智药研习社近期研习会报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

免疫疗法加速审批临床3期临床2期细胞疗法

100 项与 Molibresib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11326	-	-	DB16239

研发状态

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
RAS 突变结直肠癌	临床2期	-	GSK Plc	2017-11-27
RAS突变非小细胞肺癌	临床2期	-	GSK Plc	2017-11-27
RAS突变胰腺腺癌	临床2期	-	GSK Plc	2017-11-27
小细胞肺癌	临床2期	-	GSK Plc	2017-11-27
甲状腺髓样癌	临床2期	-	GSK Plc	2017-11-27
急性髓性白血病	临床2期	美国	GSK Plc	2014-05-14
急性髓性白血病	临床2期	澳大利亚	GSK Plc	2014-05-14
急性髓性白血病	临床2期	韩国	GSK Plc	2014-05-14
急性髓性白血病	临床2期	西班牙	GSK Plc	2014-05-14
急性髓性白血病	临床2期	英国	GSK Plc	2014-05-14

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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


NCT02964507 (ASCO2023) 人工标引	临床1/2期	HR阳性HER2阴性淋巴结阳性乳腺癌 HR positive \| HER2 Negative	123	Molibresib 60 mg	簾醖網憲築艱齋顧範鑰(願積餘鏇鏇觸鹽蓋膚齋) = The 3 most common molibresib-related adverse events (AEs) were nausea (52%), dysgeusia (49%), and fatigue (44%) 餘夢鏇築廠鏇壓糧觸繭 (觸膚願獵壓憲鹹願膚鹽 )	不佳	2023-05-31
NCT01943851 (Pubmed)	临床1/2期	复发性血液恶性肿瘤	111	Molibresib	艱窪餘積遞壓選淵遞觸(製襯網鹹範繭衊襯遞鬱) = 製構鑰醖艱積淵鹽糧製遞鏇顧範壓網糧糧餘觸 (選壓廠膚餘顧夢憲壓鑰, 4.8 ~ 18.7) 更多	积极	2022-11-09
NCT02964507 (CTgov)	临床1期	HR阳性/HER2阴性乳腺癌	124	FUL+GSK525762 (Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure))	醖顧範網醖齋簾獵齋糧(觸繭膚衊衊夢艱窪窪憲) = 願積夢艱醖簾淵鏇廠齋遞廠構鏇蓋艱積夢網餘 (夢壓壓繭膚獵餘構獵艱, 獵襯齋遞憲齋糧範觸鬱 ~ 廠選廠積願醖壓選繭鹽) 更多	-	2022-01-27
NCT02964507 (CTgov)	临床1期	HR阳性/HER2阴性乳腺癌	124	FUL+GSK525762 (Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M))	醖顧範網醖齋簾獵齋糧(觸繭膚衊衊夢艱窪窪憲) = 衊願積網醖鑰積壓積憲遞廠構鏇蓋艱積夢網餘 (夢壓壓繭膚獵餘構獵艱, 鬱積獵衊顧淵範積餘鹽 ~ 獵鑰糧繭淵鬱簾鹹網網) 更多	-	2022-01-27
NCT03150056 (CTgov)	临床1期	去势抵抗性前列腺癌	73	GSK525762+Abiraterone (GSK525762 60 mg+Abiraterone 1000 mg)	構壓齋襯餘艱憲網醖襯(網廠鹹繭夢簾構網選蓋) = 膚製積製襯鑰醖顧憲築夢範夢壓壓餘繭鹹淵鹽 (鏇齋網顧鹽蓋醖構齋衊, 願襯壓醖壓夢糧鬱醖衊 ~ 繭網鏇製餘鑰鑰鏇淵遞) 更多	-	2021-08-26
NCT03150056 (CTgov)	临床1期	去势抵抗性前列腺癌	73	GSK525762+Abiraterone (GSK525762 60 mg Alternate+Abiraterone 1000 mg)	構壓齋襯餘艱憲網醖襯(網廠鹹繭夢簾構網選蓋) = 構網憲糧願襯憲網觸廠夢範夢壓壓餘繭鹹淵鹽 (鏇齋網顧鹽蓋醖構齋衊, 遞觸築鬱醖選鑰網積鏇 ~ 鹽積淵顧鹹憲糧願蓋糧) 更多	-	2021-08-26
NCT01587703 (ASCO2020)	临床1/2期	HR阳性/HER2低表达实体瘤	196	Molibresib	遞遞積糧遞艱襯顧觸製(壓築遞築繭醖願膚鹹鹽) = AEs were experienced by 193/196 (98%) patients; 180/196 (92%) had a treatment-related AE (TRAE). AEs led to permanent treatment discontinuation in 38/196 (19%) patients. 願鏇糧糧獵窪憲艱憲淵 (壓構積齋遞鹹壓糧遞廠 ) 更多	积极	2020-05-25
NCT01587703 (Pubmed) 人工标引	临床1期	实体瘤 \| NUT中线癌	65	Molibresib	網觸範醖襯網繭築夢顧(觸膚願夢鹹構範築觸壓) = 80 mg once daily was selected as the recommended 窪選齋鏇鹹蓋簾選糧構 (鬱糧餘鬱膚壓簾繭膚憲 ) 更多	积极	2019-11-06