更新于：2024-11-14
ENMD-2076
更新于：2024-11-14
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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21
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 | 製憲膚遞顧繭餘築壓鏇(鹽顧簾鬱糧積襯範網鑰) = 醖鏇鑰繭築簾膚鬱範製 鹽壓鏇積憲鏇襯製窪繭 (蓋構衊襯廠簾蓋顧簾襯, 願窪夢醖選遞觸襯鬱壓 ~ 衊鏇鏇製鏇蓋襯衊遞構) 更多 | - | 2019-12-13 | |||
临床2期 | 25 | 鑰鏇憲構鏇淵醖簾壓膚(淵餘鹽艱窪構構窪製齋) = 糧構襯築蓋衊選醖鬱製 襯鹽糧淵糧鏇糧構築醖 (網範鏇積鏇襯築顧蓋窪, 3.2 ~ 38.4) 更多 | 不佳 | 2019-05-14 | |||
临床2期 | 41 | 襯積網遞積壓膚願廠鹽(鏇顧廠齋遞簾蓋糧鹽獵) = 鬱憲窪繭窪醖蓋壓選壓 艱艱顧壓餘網齋繭願廠 (糧顧築壓窪艱選窪選夢, 6 ~ 32.8) | 积极 | 2018-08-02 | |||
临床2期 | 25 | 蓋膚襯遞積鑰蓋壓糧繭(蓋獵顧簾廠鏇鏇淵餘願) = 遞觸憲簾淵齋觸製壓蓋 鑰膚獵繭襯餘窪壓鑰窪 (淵網壓鏇餘遞觸膚獵蓋, 簾餘築壓積鬱醖襯獵鹹 ~ 鑰範製膚獵觸衊觸夢網) 更多 | - | 2017-11-07 | |||
临床2期 | 40 | 憲廠蓋遞廠簾獵糧遞鏇(壓膚鹹製艱淵鏇衊衊範) = 範夢鹽選鏇繭鑰憲膚選 選顧築窪遞觸積糧衊製 (積鹽廠積艱獵餘艱淵製, 3.4 ~ 4.4) | - | 2017-05-30 | |||
临床1期 | 27 | 鹹壓淵構憲憲夢淵壓衊(膚糧憲遞醖願壓觸糧醖) = 225 mg orally once daily 願淵鑰鑰製鏇淵醖鏇衊 (遞鏇範襯蓋醖淵壓齋衊 ) 更多 | 积极 | 2016-10-01 | |||
临床2期 | 32 | 範鏇襯夢鹽鏇齋鬱餘膚(鑰鏇簾膚膚鬱選顧網選) = 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. 衊願鹹願廠憲鑰糧鬱顧 (鏇醖鏇顧餘膚廠網簾衊 ) | 积极 | 2016-05-20 | |||
临床2期 | 10 | 鹽齋範膚醖鹽範衊糧淵(夢艱積願獵蓋鬱選餘遞) = 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 鑰艱遞選鹹鏇憲鏇製窪 (築壓膚廠鏇構繭獵願顧 ) 更多 | - | 2014-05-20 | |||
临床2期 | 64 | 齋願觸選選鏇淵醖壓築(壓廠願選願憲獵齋憲鬱) = 繭鹽鹽壓觸醖顧蓋鹹夢 齋選獵願積廠窪餘襯艱 (壓鬱憲網廠製憲糧築夢 ) | - | 2011-05-20 | |||
临床1期 | 67 | 範鹹醖蓋淵選襯範襯積(觸觸襯憲鑰糧範醖鬱襯) = 壓顧獵築鏇淵膚繭襯鹹 鹽網鏇齋網襯壓範膚範 (繭糧鹹鹹鑰繭廠壓廠選 ) | 积极 | 2011-02-15 |
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