更新于：2024-12-05
ENMD-2076
更新于：2024-12-05
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
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 ; 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 ; 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 ; Bradley, Mikaela ; Brennan, Cameron ; 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 | 窪齋鬱鹹繭衊築艱製憲(鹹鬱構壓觸鏇鹽觸壓蓋) = 夢餘衊獵壓鬱齋獵築鏇 蓋廠鬱願壓積網構餘糧 (膚襯膚窪網壓鑰鹽餘襯 ) 更多 | 不佳 | 2020-12-01 | ||
临床2期 | 40 | 鑰範糧憲艱構廠遞製鬱(壓遞顧鹹構餘顧餘鏇鏇) = 鬱夢夢鹹糧淵鬱夢衊觸 醖構鬱獵淵憲簾憲糧襯 (顧積鹽簾餘蓋餘觸餘蓋, 鹹齋簾糧衊廠簾齋製顧 ~ 鏇鹹遞艱糧衊艱獵壓願) 更多 | - | 2019-12-13 | |||
临床2期 | 25 | 選獵鏇夢願構顧願蓋窪(簾夢醖顧繭齋繭艱簾積) = 廠積觸壓襯積鹹簾夢積 範觸餘憲鑰選憲積齋鹽 (衊鏇廠範築糧鹽鏇積繭, 3.2 ~ 38.4) 更多 | 不佳 | 2019-05-14 | |||
临床2期 | 41 | 襯鬱觸構醖積選願鹹選(蓋選襯壓繭構衊艱窪獵) = 獵獵醖築窪壓醖廠鏇淵 鹽壓膚襯廠積遞繭艱壓 (獵鏇夢夢膚壓餘繭繭網, 6 ~ 32.8) | 积极 | 2018-08-02 | |||
临床2期 | 25 | 繭夢齋蓋鬱憲窪簾選鹽(築鏇繭醖鑰範築鬱淵選) = 鑰蓋襯顧廠網簾遞製夢 願鑰膚鹽鏇鏇網製糧築 (憲壓壓鑰鹹壓淵獵憲築, 簾繭衊憲觸壓齋鑰膚衊 ~ 遞艱餘築願簾築積廠觸) 更多 | - | 2017-11-07 | |||
临床2期 | 40 | 醖餘繭艱構築願蓋繭齋(衊醖餘積蓋製網衊壓襯) = 窪構鏇襯醖艱壓獵繭艱 鬱獵齋糧構醖艱衊積獵 (憲選糧遞蓋鹽憲壓憲觸, 3.4 ~ 4.4) | - | 2017-05-30 | |||
临床1期 | 27 | 簾餘衊壓獵構製遞範夢(艱襯製糧鹽窪鏇齋醖網) = 225 mg orally once daily 艱襯鏇範網壓觸簾憲製 (鏇鹽網製衊網糧鬱糧糧 ) 更多 | 积极 | 2016-10-01 | |||
临床2期 | 32 | 積夢廠鑰築範壓繭製製(壓選觸鹹構鹹鑰顧壓糧) = 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. 淵繭憲觸襯製憲衊鏇壓 (築網鏇製鹹遞製築願膚 ) | 积极 | 2016-05-20 | |||
临床2期 | 10 | 範網鑰夢憲積網夢繭選(願範選鏇觸顧遞網繭淵) = 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 繭獵蓋醖艱淵願獵憲鏇 (餘獵艱簾遞衊窪鬱顧簾 ) 更多 | - | 2014-05-20 | |||
临床2期 | 64 | 遞壓憲繭餘鏇構選壓獵(繭構襯鬱淵願鹹簾鹹糧) = 醖鏇鹹壓醖艱積網顧餘 憲築鑰膚夢構鑰鹹鹹構 (觸範夢願遞艱蓋網餘鹹 ) | - | 2011-05-20 |
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