Mivebresib(Mivebresib) - 药物靶点：BRD4_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Mivebresib (USAN/INN)、ABB075、ABBV-075

靶点

BRD4

作用机制

BRD4抑制剂(溴结构域蛋白-4抑制剂)

治疗领域

肿瘤免疫系统疾病心血管疾病+ [5]

在研适应症-

非在研适应症

急性髓性白血病晚期癌症乳腺癌+ [6]

原研机构

AbbVie, Inc.

在研机构-

非在研机构

AbbVie, Inc.

最高研发阶段终止临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C22H19F2N3O4S

InChIKeyRDONXGFGWSSFMY-UHFFFAOYSA-N

CAS号1445993-26-9

关联

2

项与 Mivebresib 相关的临床试验

NCT04480086 / Terminated临床1期

A Phase 1b Study of Mivebresib Alone or in Combination With Ruxolitinib or Navitoclax in Subjects With Myelofibrosis

Myelofibrosis (MF) is a bone marrow illness that affects blood-forming tissues in the body. MF disturbs the body's normal production of blood cells, causing extensive scarring in the bone marrow. This leads to severe anemia, weakness, fatigue, and an enlarged spleen. The purpose of this study is to see how safe and tolerable mivebresib is, when given alone, and in combination with navitoclax or ruxolitinib, for adult participants with MF.
Mivebresib is an investigational drug being developed for the treatment of MF. The study has 4 segments - A, B, C, and D. In Segment A, the safe dosing regimen of mivebresib is identified, and then given alone as monotherapy. In Segment B, C, and D, combination therapies of mivebresib with either ruxolitinib or navitoclax are given. Adult participants with a diagnosis of MF will be enrolled. Around 130 participants will be enrolled in 60 sites worldwide.
In Segment A, participants will receive different doses and schedules of oral mivebresib tablet to identify a safe dosing regimen. Additional participants will be enrolled at the identified monotherapy dosing regimen. In Segment B, participants will receive oral ruxolitinib and mivebresib will be given as "add-on" therapy. In Segment C, participants will receive mivebresib and oral navitoclax. In Segment D, participants will receive mivebresib and ruxolitinib. Participants will receive treatment until disease progression or the participants are not able to tolerate the study drugs.
There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of treatment will be checked by medical assessments, blood and bone marrow tests, checking for side effects, and completing questionnaires.

开始日期2021-03-17

申办/合作机构

AbbVie, Inc.

NCT02391480 / Completed临床1期

A Phase 1 Study Evaluating the Safety and Pharmacokinetics of ABBV-075 in Subjects With Advanced Cancer

This is a Phase 1, first-in-human, dose escalation study in participants with advanced solid tumors to determine the pharmacokinetics, maximum tolerated dose and the recommended Phase 2 dose of ABBV-075 at different monotherapy dosing schedules. In addition the study will evaluate the safety. tolerability and the pharmacokinetics of ABBV-075 monotherapy or combination therapy in disease specific expansion cohorts.

开始日期2015-04-14

申办/合作机构

AbbVie, Inc.

100 项与 Mivebresib 相关的临床结果

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100 项与 Mivebresib 相关的转化医学

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100 项与 Mivebresib 相关的专利（医药）

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34

项与 Mivebresib 相关的文献（医药）

2024-08-02·MOLECULAR CANCER RESEARCH

MYC Family Amplification Dictates Sensitivity to BET Bromodomain Protein Inhibitor Mivebresib (ABBV075) in Small-Cell Lung Cancer

Article

作者: Murphy, Erin ; Lee, Irene ; Riehm, Jacob ; Feng, Weiguo ; Plotnik, Joshua P ; Zha, Zheng ; Sandoval, Stephanie ; Uziel, Tamar ; McClure, Ryan A ; Lu, Xin ; Lam, Lloyd T

Abstract:

Small-cell lung cancer (SCLC) accounts for nearly 15% of all lung cancers. Although patients respond to first-line therapy readily, rapid relapse is inevitable, with few treatment options in the second-line setting. Here, we describe SCLC cell lines harboring amplification of MYC and MYCN but not MYCL1 or non-amplified MYC cell lines exhibit superior sensitivity to treatment with the pan-BET bromodomain protein inhibitor mivebresib (ABBV075). Silencing MYC and MYCN partially rescued SCLC cell lines harboring these respective amplifications from the antiproliferative effects of mivebresib. Further characterization of genome-wide binding of MYC, MYCN, and MYCL1 uncovered unique enhancer and epigenetic preferences.Implications: Our study suggests that chromatin landscapes can establish cell states with unique gene expression programs, conveying sensitivity to epigenetic inhibitors such as mivebresib.

2024-06-01·Translational Andrology and Urology

BRD4 plays an antiaging role in the senescence of renal tubular epithelial cells

Article

作者: Zhu, Bei ; Bo, Yun ; Kalantar-Zadeh, Kamyar ; Wu, Jianqing ; Zhang, Yu ; Pei, Xiaohua ; Gao, Fei ; Zhang, Tao ; Zhao, Weihong ; Yong, Zhenzhu ; Zanoli, Luca ; Wei, Lu

Background:

Age-related kidney failure is often induced by a decrease in the bioavailability of tubular epithelial cells in elderly chronic kidney disease (CKD) patients. BRD4, an epigenetic regulator and a member of the bromodomain and extraterminal (BET) protein family, acts as a super-enhancer (SE) organizing and regulating genes expression during embryogenesis and cancer development. But the physiological function of BRD4 in normal cells has been less studied. This study aimed to research certain biological roles of BRD4 in the process of normal cell aging and discuss the potential mechanisms.

Methods:

In this study, we investigated the biological functions of BRD4 proteins in the aging of renal tubular cells. At first, we used a D-galactose (D-gal) and BRD4 inhibitor (Abbv-075) to replicate kidney senescence in vivo. D-gal and Abbv-075 were then used to measure the aging-related changes, such as changes in cell cycle, β-galactosidase activity, cell migration, and p16 protein expression in vitro. At last, we knocked down and over-expressed BRD4 to investigate the aging-related physiological phenomena in renal tubular cells.

Results:

In vitro, D-gal treatment induced noticeable aging-related changes such as inducing cell apoptosis and cell cycle arrest, increasing β-galactosidase activity as well as up-regulating p16 protein expression in primary human tubular epithelial cells. In the aging mice model, D-gal significantly induced renal function impairment and attenuated BRD4 protein expression. At the same time, the BRD4 inhibitor (Abbv-075) was able to mimic D-gal-induced cell senescence. In vivo, Abbv-075 also decreased kidney function and up-regulated p21 protein expression. When we knocked down the expression of BRD4, the senescence-associated β-galactosidase (SA-β-gal) activity increased dramatically, cell migration was inhibited, and the proportion of cells in the G0/G1 phase increased. Additionally, the knockdown also promoted the expression of the senescence-related proteins p16. When the renal tubular cells were overexpressed with BRD4, cell aging-related indicators were reversed in the D-gal-induced cell aging model.

Conclusions:

BRD4 appears to have an active role in the aging of renal tubular cells in vivo and in vitro. The findings also suggest that BRD4 inhibitors have potential nephrotoxic effects for oncology treatment. BRD4 may be a potential therapeutic biomarker and drug target for aging-related kidney diseases, which warrants additional studies.

2023-12-01·Cancer research

Epigenetic Cooperativity as a Therapeutic Vulnerability in Cancer

Article

作者: Kazansky, Yaniv ; Kentsis, Alex

Abstract:

NUT carcinoma (NC) is one of the most common types of undifferentiated carcinomas affecting young adults with a dismal prognosis. NUT carcinomas often involve chromosomal translocations, leading to the production of BRD4-NUT fusion protein that generates large domains of hyperactive chromatin and activates oncogenic gene expression. Bromodomain and extraterminal domain (BET) bromodomain inhibitors offer a direct means to block BRD4-mediated gene activation but have shown limited clinical efficacy in patients. In this issue of Cancer Research, Huang and colleagues report an unexpected discovery of a synthetic lethal NC dependency on Polycomb repressive complex 2 (PRC2)–mediated gene repression, including EZH2, the catalytic subunit of PRC2. EZH2 is highly expressed in NC patient tumors and a specific inhibitor of its methyltransferase activity, tazemetostat, exhibits potent antitumor cell activity. While the repressed and activated chromatin domains in NC cells are distinct, the resultant gene expression changes exhibit convergent features, including dysregulation of CDKN2A and the E2F-RB1 axis. As a result, combined treatment of NC tumors with tazemetostat and the BET inhibitor mivebresib produces marked antitumor therapeutic synergy in vitro and in vivo, associated with enhanced suppression of RB1 function through convergent remodeling of NC gene expression. This study advances epigenetic cooperativity as a distinct mode of gene expression dysregulation in NC and nominates a compelling combination epigenetic strategy for investigation in clinical trials for patients.See related article by Huang et al., p. 3956

100 项与 Mivebresib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11479	-	-	-

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
骨髓纤维化	临床1期	美国	AbbVie, Inc.	2021-03-17
骨髓纤维化	临床1期	南非	AbbVie, Inc.	2021-03-17
骨髓纤维化	临床1期	韩国	AbbVie, Inc.	2021-03-17
原发性骨髓纤维化	临床1期	美国	AbbVie, Inc.	2021-03-17
原发性骨髓纤维化	临床1期	南非	AbbVie, Inc.	2021-03-17
原发性骨髓纤维化	临床1期	韩国	AbbVie, Inc.	2021-03-17
急性髓性白血病	临床1期	美国	AbbVie, Inc.	2015-04-14
晚期癌症	临床1期	美国	AbbVie, Inc.	2015-04-14
乳腺癌	临床1期	美国	AbbVie, Inc.	2015-04-14
多发性骨髓瘤	临床1期	美国	AbbVie, Inc.	2015-04-14

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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


NCT02391480 (Pubmed \| Cancer) 人工标引	临床1期	急性髓性白血病	44	mivebresib	簾壓觸廠遞網鬱願顧糧(窪鬱範願憲遞構艱構簾) = 簾網膚夢網願積壓糧壓鬱齋鏇襯衊蓋繭糧觸遞 (餘築觸鑰願齋膚膚積鬱 ) 更多	积极	2021-08-15
NCT02391480 (Pubmed \| Cancer) 人工标引	临床1期	急性髓性白血病	44	venetoclax+mivebresib	簾壓觸廠遞網鬱願顧糧(窪鬱範願憲遞構艱構簾) = 顧蓋簾醖願鏇膚網衊窪鬱齋鏇襯衊蓋繭糧觸遞 (餘築觸鑰願齋膚膚積鬱 ) 更多	积极	2021-08-15
NCT02391480 (Pubmed \| Clin Cancer Res) 人工标引	临床2期	实体瘤	84	Mivebresib (14% uveal melanoma; 11% colorectal; 11% breast; 8% pancreatic; 7% head/neck; 49% others)	壓積窪憲壓壓醖齋糧鏇(廠鑰選願膚憲觸遞製觸) = 壓淵製製遞製鑰築蓋淵積網築艱遞獵願壓網襯 (蓋願鹹鹽願淵獵糧淵膚, 1.8 ~ 1.9) 更多	积极	2019-11-01
NCT02391480 (Pubmed \| Clin Cancer Res) 人工标引	临床2期	实体瘤	84	Mivebresib (prostate cancer)	-	积极	2019-11-01
NCT02391480 (EHA2019)	临床1期	复发性急性髓细胞白血病	41	Mivebresib monotherapy	遞選鑰觸遞艱廠簾顧衊(鏇鏇鹹鹹願鏇鏇顧膚衊) = 衊憲製鏇鏇夢衊蓋壓製糧艱獵膚膚鏇鹹鹹範鑰 (餘鬱鏇憲鏇夢範顧繭鏇 ) 更多	-	2019-06-14
NCT02391480 (ASCO2019)	临床1期	葡萄膜黑色素瘤	10	Mivebresib (ABBV-075)	鬱壓窪齋鏇艱顧齋顧壓(繭艱窪廠淵廠餘鑰襯夢) = 9 patients experienced a treatment-emergent adverse event (TEAE), most commonly (≥40% patient incidence), dysgeusia (60%), thrombocytopenia and nausea (40%, each) 餘鏇選憲鬱願顧獵膚製 (構鏇鹹餘選製鑰鑰鬱鏇 )	-	2019-05-26
NCT02391480 (ASCO2019)	临床1期	复发性急性髓细胞白血病	41	Mivebresib monotherapy	獵蓋積艱鹹鬱壓獵選壓(鏇衊齋築願構餘窪製壓) = 鏇構夢獵醖蓋鑰繭廠襯鹽艱範淵繭鏇膚艱艱選 (鹹繭夢簾製壓鏇淵鬱膚 ) 更多	积极	2019-05-26
NCT02391480 (ASCO2019)	临床1期	复发性急性髓细胞白血病	41	Mivebresib combined with venetoclax	繭衊糧夢鏇廠顧獵醖膚(積壓構選鹹鹹艱廠艱獵) = 壓蓋憲艱網製繭齋襯獵艱壓遞膚糧鹹襯齋廠鬱 (獵廠窪觸網範繭簾範襯 ) 更多	积极	2019-05-26
NCT02391480 (ASCO2018)	临床1期	复发性急性髓细胞白血病	19	ABBV-075 monotherapy	鑰襯餘築淵艱醖壓築遞(襯鏇夢窪鏇窪齋衊艱顧) = 11 衊鹽壓願鏇簾鏇鬱衊憲 (窪觸壓網繭繭選蓋遞糧 ) 更多	积极	2018-06-01
NCT02391480 (M14-546, ASCO2018)	临床1期	实体瘤	72	ABBV-075	鹹醖構鹹鏇獵繭鹹鏇觸(艱鹹憲製壓膚網鹹遞鬱) = Dose-limiting toxicities were aspartate aminotransferase elevation 網鏇繭壓醖鹹觸範夢鹹 (鑰窪繭衊鑰鬱鹽餘糧膚 ) 更多	-	2018-06-01
NCT02391480 (M14-546, ASCO2018)	临床1期	葡萄膜黑色素瘤	10	ABBV-075	範鬱遞繭選鹹襯襯襯積(壓醖糧鬱獵鹽窪窪膚構) = 50% 遞觸齋壓廠夢繭構餘鬱 (願鬱餘構鬱蓋鬱衊膚積 ) 更多	-	2018-06-01
NCT02391480 (ASCO2018)	临床1期	实体瘤	72	ABBV-075	願顧餘壓廠齋壓憲壓鹹(廠襯範積憲觸遞製鏇觸) = 15.3% vs none 遞襯廠夢鹹獵構簾顧餘 (鏇築廠鹹艱膚夢鬱範積 ) 更多	积极	2018-06-01