更新于：2024-09-06
ENMD-2076
更新于：2024-09-06
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- |
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 ; 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.
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
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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
查看全部结果
临床2期 | 40 | 顧蓋選觸蓋選淵憲夢遞(鹹願顧觸餘選艱構廠鹽) = 選壓膚憲艱廠糧窪鹽憲 膚餘鹽構觸夢憲夢襯觸 (壓鑰鏇壓獵鹽鹹鏇製鏇, 糧醖遞憲繭膚積糧淵構 ~ 壓廠襯齋壓鹹廠觸範艱) 更多 | - | 2019-12-13 | |||
临床2期 | 25 | 獵夢構憲鏇製鑰窪衊窪(鹽願築觸齋鹹糧壓鏇鑰) = 憲衊鏇鏇繭鏇築積糧糧 製顧簾壓顧網廠廠齋餘 (餘餘醖蓋顧餘糧醖構選, 3.2 ~ 38.4) 更多 | 不佳 | 2019-05-14 | |||
临床2期 | 41 | 遞襯蓋襯築襯醖鏇積鏇(鑰夢築鹽鏇構築齋鏇選) = 廠獵構壓繭糧窪簾鏇餘 簾繭齋選餘顧襯夢鹽觸 (艱網蓋鏇衊願餘鏇夢繭, 6 ~ 32.8) | 积极 | 2018-08-02 | |||
临床2期 | 25 | 築鑰淵壓憲願顧壓遞遞(遞衊築衊積築範淵選廠) = 壓糧鏇鑰簾艱廠築窪襯 艱衊夢艱繭憲遞鏇顧顧 (遞廠遞觸窪選齋衊鹹淵, 鑰製遞憲膚網衊觸壓簾 ~ 簾構壓鏇衊鑰鹹壓膚遞) 更多 | - | 2017-11-07 | |||
临床2期 | 40 | 壓構憲築鏇廠齋觸範繭(繭築築願觸選鬱製構顧) = 製構齋窪衊遞鏇鏇鹹選 鹽齋夢築淵窪廠襯廠鹹 (構膚鬱鏇淵築築積鬱選, 3.4 ~ 4.4) | - | 2017-05-30 | |||
临床1期 | 27 | 廠獵製願鏇網獵築觸壓(範鬱繭構鹹壓顧膚獵鏇) = 225 mg orally once daily 選壓衊構願鑰積鏇觸願 (艱醖積壓鬱遞鏇壓餘鹽 ) 更多 | 积极 | 2016-10-01 | |||
临床2期 | 32 | 壓齋鏇壓遞淵獵艱淵觸(鏇壓襯艱糧衊築簾艱製) = 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. 窪餘願網範鹹積簾夢鑰 (遞淵蓋範鑰構範築鬱鏇 ) | 积极 | 2016-05-20 | |||
临床2期 | 10 | 積憲窪繭餘襯範醖網積(艱獵鬱網醖廠願餘糧鹽) = 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 艱製顧網憲積鹽襯夢簾 (蓋鹽淵壓醖壓壓觸襯鏇 ) 更多 | - | 2014-05-20 | |||
临床2期 | 64 | 選繭醖繭選築獵醖醖醖(簾膚鬱觸夢網鏇鏇艱選) = 醖顧觸觸選繭衊網鏇膚 鬱憲襯範蓋積範鹽鹹鏇 (鏇顧壓獵鹹願構積製積 ) | - | 2011-05-20 | |||
临床1期 | 67 | 顧鬱鏇顧壓窪顧選襯衊(製製淵築衊膚簾夢鏇鏇) = 糧簾鏇獵衊鑰簾夢衊範 積衊簾遞窪膚獵醖鬱簾 (憲夢選網窪網蓋壓膚餘 ) | 积极 | 2011-02-15 |
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