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更新于：2025-01-10
ENMD-2076
更新于：2025-01-10
概要
基本信息
非在研机构- |
最高研发阶段临床2期 |
首次获批日期- |
最高研发阶段(中国)临床2期 |
特殊审评- |
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结构/序列
分子式C25H31N7O6 |
InChIKeyKGWWHPZQLVVAPT-STTJLUEPSA-N |
CAS号1453868-32-0 |
关联
9
项与 ENMD-2076 相关的临床试验NCT02234986
A Phase 2, Multi-center, Open-label Study of Oral ENMD-2076 for the Treatment of Patients With Advanced Fibrolamellar Carcinoma (FLC)
CTR20150075
一项ENMD-2076治疗局部复发或转移的三阴性乳腺癌晚期患者的安全性和耐受性的IIa期临床试验
NCT01914510
Phase II Study of Oral ENMD-2076 Administered to Patients With Ovarian Clear Cell Carcinomas
100 项与 ENMD-2076 相关的临床结果
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100 项与 ENMD-2076 相关的转化医学
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100 项与 ENMD-2076 相关的专利（医药）
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24
项与 ENMD-2076 相关的文献（医药）2023-08-01European journal of medicinal chemistry
Discovery of a first-in-class Aurora A covalent inhibitor for the treatment of triple negative breast cancer
Article
作者: Zhu, Chengchen ; Lu, Gui ; Chan, Albert S C ; Zhang, Bin
Aurora kinases, which belong to the serine/threonine protein family, play critical roles in the regulation of the cell cycle and mitotic spindle assembly. They are frequently highly expressed in various types of tumors, and the use of selective Aurora kinase inhibitors has become a potential treatment option for cancer therapy. Despite the development of some reversible Aurora kinase inhibitors, none has been approved for clinical use yet. In this study, we report the discovery of the first-in-class irreversible Aurora A covalent inhibitors that target a cysteine residue at the substrate binding site. These inhibitors were characterized in enzymatic and cellular assays, and 11c exhibited selective inhibition to normal and cancer cells, as well as to Aurora A and B kinases. The covalent binding of 11c to Aurora A was confirmed by SPR, MS, and enzyme kinetic analysis, and Cys290-mediated covalent inhibition was supported through a bottom-up analysis of inhibitor-modified targets. Moreover, Western blotting assays were conducted on cells and tissues, and cellular thermal shift assays (CETSA) were further performed on cells to demonstrate the selectivity to Aurora A kinase. 11c displayed comparable therapeutic efficacy in an MDA-MB-231 xenograft mouse model relative to the positive control ENMD-2076, while requiring only half the dose of ENMD-2076. These results confirmed that 11c may be a promising drug candidate for the treatment of triple negative breast cancer (TNBC). Our work may provide a new perspective on the design of covalent inhibitors of Aurora kinase.
2022-10-01Clinical Lymphoma Myeloma & Leukemia
AML-377 A “Designed” High-Throughput Drug Screening Strategy Identifies Aurora Kinase A Inhibitors as Promising Preclinical Candidates for the Treatment of NPM1-Mutated AML
Article
作者: Neuenschwander, Martin ; Martelli, Maria Paola ; Pierangeli, Sara ; Sabino, Marcella ; Ferrari, Alessio ; Donnini, Serena ; Tini, Valentina ; Silvestri, Serenella ; Mezzasoma, Federica ; Ranieri, Roberta ; Kries, Jens Peter von ; Falini, Brunangelo ; Spinozzi, Giulio ; Gionfriddo, Ilaria ; Milano, Francesca ; Kleissle, Sabrina
CONTEXT:
Nucleophosmin (NPM1)-mutated acute myeloid leukemia (AML) accounts for one-third of adult AML and displays distinctive biological and clinical features. Despite its chemo-sensitivity and a relatively favorable prognosis, this leukemia lacks any specific therapies. Because NPM1 mutant protein is not druggable, targeting its non-oncogene addictions and its specific vulnerabilities can represent an alternative option for identifying a tailored therapy for NPM1-mutated AML.
OBJECTIVE:
We performed a high-throughput screening (HTS) of different chemical compounds and drug libraries to find drugs or compounds 'synthetically lethal' with NPM1 mutation and/or showing more selective activity in AML with NPM1 mutation.
METHODS:
In collaboration with the Screening Unit of Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP; (Berlin, Germany), we performed an HTS of 38720 drugs/compounds in a 384-well format. The assay readout was cellular metabolism/viability by CellTiter Blue assay at 48 hours. The screening was properly designed in 2 steps to increase efficiency, exclude compounds with general toxicity, and identify compounds ('hits') selectively active against the only two available NPM1-mutated AML cell lines, OCI-AML3 and IMS-M2, but not against wild-type controls.
RESULTS:
Sixty-two hit compounds that met qHTS threshold criteria were rescreened in a dose-response experiment. From this analysis, we obtained 37 compounds able to selectively kill IMS-M2 (IMS-M2 %viability <50 vs. OCI-AML2 %viability >75). We focused on Aurora kinase A inhibitors (AURKAi) because 4 of the selective compounds were directed against this kinase. In the validation assay, 2 compounds (MK-5108 and MK-8745) were confirmed as more active against NPM1-mutated than NPM1-wild-type AML cells by either CyQUANT or apoptosis assay. Strikingly, we confirmed selectivity for two additional AURKAi (Alisertib and ENMD-2076, both isoform-selective inhibitors of AURKA) that were not included in the screening library. The AURKAi were also effective in reducing tumor burden in NPM1-mutated PDX cell models and provided a survival advantage compared with vehicle-treated mice (60 vs. 32 days, P=0.005).
CONCLUSIONS:
We demonstrated that using HTS can considerably shorten drug discovery time scales, leading to the identification of promising lead compounds. Our study is the first to provide preclinical evidence of the antileukemic activity of AURKAi, with particular focus on NPM1-mutated AML.
2020-12-01The oncologist2区 · 医学
Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma
2区 · 医学
Article
作者: Ren, Ken ; O'Neill, Allison F. ; Kingham, Peter T. ; Kobos, Rachel ; Beg, Muhammad S. ; Venook, Alan P. ; Leong, Stephen ; Hoti, Emir ; Yopp, Adam ; Bradley, Mikaela ; Brennan, Cameron ; Mayer, Robert ; Abou-Alfa, Ghassan K. ; Ly, Michele ; Crown, John ; Gordan, John D. ; Valentino, Emily ; LaQuaglia, Michael ; Leonard, Gregory ; Zukiwski, Alexander ; Harding, James J. ; Markowitz, David ; Basturk, Olca
Abstract:
Lessons Learned:
The fibrolamellar carcinoma-associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and, thus, overexpression of Aurora kinase A. ENMD-2076 showed a favorable toxicity profile. The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support further evaluation of ENMD-2076 as single agent. Future studies will depend on the simultaneous targeting approach of DNAJB1-PRKACA and the critical downstream components.
Background:
Fibrolamellar carcinoma (FLC) represents approximately 0.85% of liver cancers. The associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and overexpression of Aurora kinase A (AURKA). ENMD-2076 is a selective anti-AURKA inhibitor.
Methods:
Patients aged >12 years with pathologically confirmed incurable FLC, with measurable disease, Eastern Cooperative Oncology Group performance status 0–2 or Lansky 70–100, and adequate organ function were eligible. Patients were prescribed ENMD-2076 based on body surface area. The primary endpoint was overall objective response rate by RECIST v1.1, with a null hypothesis of true response rate of 2% versus one-sided alternative of 15%. Secondary endpoints included 6-month progression-free survival (PFS) rate (Fig. 1), median PFS, time to progression (TTP), and overall survival (OS). Safety was evaluated throughout the study.
Results:
Of 35 patients who enrolled and received treatment, 1 (3%) had a partial response (PR) and 20 (57%) had stable disease (SD). Median TTP, PFS, and OS were 5, 3.9, and 19 months, respectively. The most frequently reported drug-related serious adverse event was hypertension in three patients. Three deaths were reported on-study—two due to disease progression and one due to pulmonary embolism not related to ENMD-2076.
Conclusion:
The study provided no rationale for further studying ENMD-2076 as a single agent in FLC.
100 项与 ENMD-2076 相关的药物交易
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 晚期肝细胞癌 | 临床2期 | 美国 | 2015-10-01 | |
| 纤维板层肝细胞癌 | 临床2期 | 美国 | 2015-10-01 | |
| 三阴性乳腺癌 | 临床2期 | 美国 | 2012-07-01 | |
| 三阴性乳腺癌 | 临床2期 | 中国 | 2012-07-01 | |
| 输卵管癌 | 临床2期 | 美国 | 2010-04-01 | |
| 输卵管癌 | 临床2期 | 加拿大 | 2010-04-01 | |
| 腹膜癌 | 临床2期 | 美国 | 2010-04-01 | |
| 腹膜癌 | 临床2期 | 加拿大 | 2010-04-01 | |
| 铂耐药性卵巢癌 | 临床2期 | 美国 | 2010-04-01 | |
| 铂耐药性卵巢癌 | 临床2期 | 加拿大 | 2010-04-01 |
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临床结果
临床结果
适应症
分期
评价
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临床2期 | 纤维板层肝细胞癌 DNAJB1-PRKACA gene fusion transcript RNA | Aurora kinase A | 35 | 夢餘顧範憲願鹹鑰夢顧(蓋衊艱齋蓋夢蓋糧鑰壓) = 顧壓廠鬱廠觸窪蓋蓋淵 齋齋膚餘鹽醖積鑰餘製 (簾遞願簾衊遞衊膚淵窪 ) 更多 | 不佳 | 2020-12-01 | ||
临床2期 | 40 | 憲壓餘鏇憲壓壓繭鹽簾(襯願鏇衊顧鏇壓淵齋觸) = 齋憲網選淵鏇醖餘艱壓 淵醖積餘築淵網衊範衊 (構膚餘獵構壓構網膚簾, 窪製選膚鬱憲壓鬱壓窪 ~ 壓鹹網艱選壓觸選糧膚) 更多 | - | 2019-12-13 | |||
临床2期 | 25 | 範獵膚憲廠鏇醖鹽築憲(鑰夢淵積夢積獵網製壓) = 觸糧願獵鏇醖築選蓋糧 餘顧衊憲蓋壓網顧繭憲 (鏇鹽蓋膚醖糧範艱膚廠, 3.2 ~ 38.4) 更多 | 不佳 | 2019-05-14 | |||
临床2期 | 41 | 壓網膚醖淵襯獵衊淵獵(膚鑰憲鬱繭鏇餘繭遞構) = 夢繭製網壓淵膚壓鹹艱 顧網糧築簾顧鹹淵衊積 (艱壓鹽艱鑰範鏇艱糧積, 6 ~ 32.8) | 积极 | 2018-08-02 | |||
临床2期 | 41 | 鏇鏇襯餘製構艱艱選願(艱艱構鏇艱鑰製蓋顧觸) = 廠顧餘淵廠壓鑰遞鏇積 網鏇築簾觸齋夢膚製夢 (鹽構獵鹹願窪艱餘夢齋, 6% ~ 32.8%) | 积极 | 2018-02-15 | |||
临床2期 | 25 | 齋鏇簾艱繭築壓廠積糧(醖憲夢願夢鹹範鹹築壓) = 夢繭積憲衊蓋築餘淵淵 艱遞廠窪繭鏇網積網願 (糧遞鏇鑰餘願構願衊簾, 簾築淵憲願鑰願範繭製 ~ 觸壓窪網鹽顧餘鬱願遞) 更多 | - | 2017-11-07 | |||
临床2期 | 40 | 積膚繭廠壓製積製鹽壓(範鹽餘獵鹹願顧繭膚願) = 獵製憲選網淵鬱壓淵夢 窪簾淵鹽簾簾築鑰簾鹹 (窪選築觸膚鬱夢鹹顧憲, 3.4 ~ 4.4) | - | 2017-05-30 | |||
临床1期 | 27 | 獵簾糧蓋夢願齋獵繭壓(簾淵蓋網鏇繭鬱遞壓願) = 225 mg orally once daily 鏇鬱窪鹹醖夢鬱衊淵製 (窪鑰鏇製製衊網鏇繭積 ) 更多 | 积极 | 2016-10-01 | |||
临床2期 | 32 | 製憲鹽鑰醖構鬱鹽選構(鹽夢衊積襯憲廠構製積) = Drug-related adverse events (AEs) occurred in 24/28 (86%) evaluable pts, the most common being Grade (Gr) 1/2 fatigue, nausea/vomiting, hypertension and diarrhea. Gr ≥ 3 AEs were reported in 46% of pts. AE resulted in dose reductions in 11 pts (39%) and led to treatment discontinuation in 3. 顧觸簾築觸艱構憲襯鏇 (衊觸糧鏇網鑰襯齋蓋構 ) | 积极 | 2016-05-20 | |||
临床2期 | 10 | 觸願製積淵衊願鏇襯鏇(積襯鏇夢鹹艱膚壓繭鏇) = 1 pt developed PRES presenting as grade 4 loss of consciousness at Cycle 1 Day 15 required ICU admission. Full neurological recovery was attained after cessation of treatment 壓獵鑰築夢簾蓋遞選獵 (獵積願淵窪夢窪壓夢壓 ) 更多 | - | 2014-05-20 |
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