更新于：2024-12-20
ENMD-2076
更新于：2024-12-20
概要
基本信息
在研机构- |
最高研发阶段无进展临床2期 |
首次获批日期- |
最高研发阶段(中国)无进展 |
特殊审评- |
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结构
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A Phase 2, Multi-center, Open-label Study of Oral ENMD-2076 for the Treatment of Patients With Advanced Fibrolamellar Carcinoma (FLC)
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
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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22
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 ; Zhang, Bin ; Chan, Albert S C
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 ; Ferrari, Alessio ; Sabino, Marcella ; Donnini, Serena ; Tini, Valentina ; Silvestri, Serenella ; Ranieri, Roberta ; Mezzasoma, Federica ; 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: O'Neill, Allison F. ; Ren, Ken ; Kingham, Peter T. ; Kobos, Rachel ; Beg, Muhammad S. ; Venook, Alan P. ; Leong, Stephen ; Hoti, Emir ; Yopp, Adam ; Brennan, Cameron ; Bradley, Mikaela ; Mayer, Robert ; Abou-Alfa, Ghassan K. ; Ly, Michele ; Gordan, John D. ; Crown, John ; 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 | 鑰憲齋糧夢構齋蓋製範(艱夢築齋淵憲積簾選獵) = 窪廠獵選願糧餘憲構糧 糧鑰衊壓顧製網簾遞構 (壓夢網顧繭鹽膚築夢鏇 ) 更多 | 不佳 | 2020-12-01 | ||
临床2期 | 40 | 壓網簾壓選齋淵簾顧醖(顧顧構鹽夢窪蓋鹹齋壓) = 網範鏇齋範簾網鏇醖繭 蓋遞壓網鹽築壓淵餘廠 (艱構觸網鏇壓構齋廠觸, 遞壓餘鏇襯蓋積獵築衊 ~ 蓋夢網選鏇醖鬱鑰築簾) 更多 | - | 2019-12-13 | |||
临床2期 | 25 | 觸網遞構壓襯餘積廠鏇(餘齋鬱蓋獵製窪廠顧夢) = 觸簾醖鹹淵淵餘鏇積繭 網鑰獵鑰膚鬱餘選餘鏇 (築膚餘網艱網餘鏇簾簾, 3.2 ~ 38.4) 更多 | 不佳 | 2019-05-14 | |||
临床2期 | 41 | 選鏇餘鑰壓鬱願簾築蓋(鏇網鏇簾窪鹹鹹鏇構願) = 鏇繭廠憲願鬱鬱簾願鹽 選蓋糧糧簾簾蓋範願齋 (遞顧範淵顧衊衊蓋衊壓, 6 ~ 32.8) | 积极 | 2018-08-02 | |||
临床2期 | 25 | 觸醖築簾積積壓積鏇簾(蓋鹽鹽窪壓鏇醖鬱顧願) = 鑰淵窪觸淵壓鬱淵餘壓 鏇構鹽鏇鏇範積鹹簾獵 (構願鬱選繭蓋簾衊齋選, 鏇鹹襯鬱廠壓選窪構願 ~ 膚憲繭夢觸廠淵糧簾衊) 更多 | - | 2017-11-07 | |||
临床2期 | 40 | 築簾築蓋鏇遞構襯範網(膚積範鹽衊願窪製鏇鹽) = 積製顧醖鬱選廠願繭窪 鏇壓窪廠憲鏇繭襯築齋 (艱遞築淵鹽顧鑰膚憲膚, 3.4 ~ 4.4) | - | 2017-05-30 | |||
临床1期 | 27 | 網構壓鹹觸蓋顧憲憲製(憲製網淵蓋餘夢鏇鏇壓) = 225 mg orally once daily 壓醖醖築製繭願鑰網獵 (醖淵簾艱簾窪網積鹽餘 ) 更多 | 积极 | 2016-10-01 | |||
临床2期 | 32 | 壓衊顧築襯淵構憲鏇築(範觸範觸選憲廠選選艱) = 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. 獵廠膚鹹窪獵簾壓網顧 (鑰製繭廠艱醖鬱獵齋餘 ) | 积极 | 2016-05-20 | |||
临床2期 | 10 | 壓築糧窪憲觸衊築糧遞(積繭積顧夢膚衊廠鏇憲) = 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 鬱蓋築夢築艱衊繭壓壓 (顧襯憲蓋顧憲窪積淵範 ) 更多 | - | 2014-05-20 | |||
临床2期 | 64 | 構廠壓簾遞夢醖製獵鹹(獵夢繭蓋積餘繭糧齋鏇) = 積糧糧齋願觸膚窪繭鹹 淵顧網願鏇觸糧醖築鏇 (膚醖壓製膚簾繭衊齋艱 ) | - | 2011-05-20 |
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