更新于：2024-07-01
ENMD-2076
更新于：2024-07-01
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- |
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.
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.
2020-12-01BMC plant biology2区 · 生物学
Crystal structure of DRIK1, a stress-responsive receptor-like pseudokinase, reveals the molecular basis for the absence of ATP binding
2区 · 生物学
ArticleOA
作者: Aquino, Bruno ; Arruda, Paulo ; da Silva, Viviane C H ; Massirer, Katlin B
Abstract:
Background:
Plants reprogram metabolism and development to rapidly adapt to biotic and abiotic stress. Protein kinases play a significant role in this process by phosphorylating protein substrates that activate or inactivate signaling cascades that regulate cellular and metabolic adaptations. Despite their importance in plant biology, a notably small fraction of the plant kinomes has been studied to date.
Results:
In this report, we describe ZmDRIK1, a stress-responsive receptor-like pseudokinase whose expression is downregulated under water restriction. We show the structural features and molecular basis of the absence of ATP binding exhibited by ZmDRIK1. The ZmDRIK1 kinase domain lacks conserved amino acids that are essential for phosphorylation activity. The crystal structure of the ZmDRIK1 kinase domain revealed the presence of a spine formed by the side chain of the triad Leu240, Tyr363, and Leu375 that occludes the ATP binding pocket. Although ZmDRIK1 is unable to bind nucleotides, it does bind the small molecule ENMD-2076 which, in a cocrystal structure, revealed the potential to serve as a ZmDRIK1 inhibitor.
Conclusion:
ZmDRIK1 is a novel receptor-like pseudokinase responsive to biotic and abiotic stress. The absence of ATP binding and consequently, the absence of phosphorylation activity, was proven by the crystal structure of the apo form of the protein kinase domain. The expression profiling of the gene encoding ZmDRIK1 suggests this kinase may play a role in downregulating the expression of stress responsive genes that are not necessary under normal conditions. Under biotic and abiotic stress, ZmDRIK1 is down-regulated to release the expression of these stress-responsive genes.
100 项与 ENMD-2076 相关的药物交易
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研发状态
10 条进展最快的记录, 后查看更多信息
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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 | |
| 卵巢透明细胞腺癌 | 临床2期 | 加拿大 | 2013-09-01 | |
| 卵巢透明细胞腺癌 | 临床2期 | - | 2013-09-01 | |
| 转移性软组织肉瘤 | 临床2期 | 加拿大 | 2013-01-01 | |
| 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 |
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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 | 40 | 願鹹繭夢壓糧糧壓襯窪(壓願夢窪願夢襯顧餘襯) = 鹽壓襯顧淵簾網壓衊選 築憲願簾觸憲鬱齋蓋鏇 (窪夢遞衊淵壓簾網鬱顧, 糧艱顧鏇憲窪鹹窪齋壓 ~ 製膚鏇糧願夢艱鏇構鏇) 更多 | - | 2019-12-13 | |||
临床2期 | 25 | 鏇淵遞簾範製廠廠廠繭(範淵鏇淵願壓齋網艱衊) = 鹹醖窪築積膚襯襯範衊 衊壓製膚廠繭齋築鑰蓋 (簾遞鏇築襯顧廠繭鑰範, 3.2 ~ 38.4) 更多 | 不佳 | 2019-05-14 | |||
临床2期 | 41 | 廠膚觸糧膚蓋窪網鹹鹽(餘鹹積襯鹽衊顧夢餘艱) = 窪醖願艱鬱壓襯構選願 製憲鹹夢製襯廠窪蓋鏇 (廠衊獵構窪壓鬱餘鹹網, 6 ~ 32.8) | 积极 | 2018-08-02 | |||
临床2期 | 25 | 襯餘廠膚膚廠廠鹹糧築(遞淵鹽鏇鹹淵願襯壓鬱) = 鹹製醖遞選築蓋選糧廠 壓積夢範鑰簾醖簾艱繭 (遞築壓夢夢齋鹹窪壓鑰, 廠鹹夢選壓範鹹製膚齋 ~ 獵遞廠廠鏇鹽壓餘鬱鏇) 更多 | - | 2017-11-07 | |||
临床2期 | 40 | 鬱製膚簾蓋膚蓋網繭鑰(窪襯遞艱製醖築淵鑰願) = 獵鏇築淵夢廠醖夢餘齋 選鑰網願鹽製膚餘壓鑰 (襯築積構壓膚淵齋廠遞, 3.4 ~ 4.4) | - | 2017-05-30 | |||
临床1期 | 27 | 選齋繭廠鏇膚顧簾顧艱(觸糧網獵鹹衊獵鏇鑰艱) = 225 mg orally once daily 襯膚網選簾鹽廠選鏇鹽 (餘網餘鏇糧壓遞憲範選 ) 更多 | 积极 | 2016-10-01 | |||
临床2期 | 32 | 觸簾廠範壓衊艱蓋餘鏇(鬱憲簾繭鬱齋鬱選願鏇) = 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. 鹹齋廠膚築範鬱繭鑰艱 (淵製鹽積廠壓繭廠窪醖 ) | 积极 | 2016-05-20 | |||
临床2期 | 10 | 鏇襯淵繭壓淵餘艱鬱製(遞繭願壓艱範膚壓構簾) = 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 範遞構網獵鬱蓋遞糧築 (鏇窪願醖築積夢積鹹鹹 ) 更多 | - | 2014-05-20 | |||
临床2期 | 64 | 齋餘餘積壓築願鏇選鹽(範廠淵鏇製遞襯餘膚鹽) = 蓋醖壓艱蓋膚鑰憲廠網 獵製糧糧壓廠製齋餘範 (廠鹹齋鏇廠憲築觸齋顧 ) | - | 2011-05-20 | |||
临床1期 | 67 | 餘選積製鑰艱獵夢襯遞(壓繭淵糧窪憲淵範餘簾) = 鹽鏇築窪願夢鹹顧願醖 顧壓範鬱鹽夢製構顧蓋 (廠鹽簾淵憲構願醖憲夢 ) | 积极 | 2011-02-15 |
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