AT-9283(AT-9283) - 药物靶点：Aurora A x Aurora B x Bcr-Abl T315I x FLT3 x JAK2_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

Aurora A x Aurora B x Bcr-Abl T315I x FLT3 x JAK2

作用机制

Aurora A抑制剂(丝氨酸/苏氨酸蛋白激酶Aurora-A抑制剂)、Aurora B抑制剂(丝氨酸/苏氨酸蛋白激酶Aurora-B抑制剂)、Bcr-Abl T315I抑制剂(bcr-abl酪氨酸激酶T315I抑制剂)

+ [2]

治疗领域

肿瘤免疫系统疾病心血管疾病+ [3]

在研适应症-

非在研适应症

急性白血病急性淋巴细胞白血病急性髓性白血病+ [7]

原研机构

Astex Therapeutics Ltd.

在研机构-

非在研机构

Astex Pharmaceuticals, Inc.

Astex Therapeutics Ltd.

Cancer Research UK

+ [1]

最高研发阶段终止临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C19H24ClN7O2

InChIKeyNHFNYIVVGIXBPD-UHFFFAOYSA-N

CAS号896466-61-8

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关联

3

项与 AT-9283 相关的临床试验

NCT01431664

/ Completed临床1期IIT

A Cancer Research UK Phase I/IIa Trial of AT9283 (A Selective Inhibitor of Aurora Kinases) Given Over 72 Hours Every 21 Days Via Intravenous Infusion in Children and Adolescents Aged 6 Months to 18 Years With Relapsed and Refractory Acute Leukemia

RATIONALE: AT9283 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
PURPOSE: This phase I/IIa clinical trial is studying the side effects and best dose of AT9283 in treating young patients with relapsed or refractory acute leukemia.

开始日期2011-09-01

申办/合作机构

Cancer Research UK

NCT01145989

/ Completed临床2期IIT

A Phase II Study of AT9283 in Patients With Relapsed or Refractory Multiple Myeloma

The purpose of this study is to find out whether the new drug AT9283 will slow the growth of multiple myeloma. Side effects of AT9283 will also be closely monitored.

开始日期2011-02-15

申办/合作机构

NCIC Clinical Trials Group

[+1]

NCT00522990

/ Terminated临床1/2期

A Phase I/IIa Open-label Study to Assess the Safety, Tolerability and Preliminary Efficacy of AT9283, a Small Molecule Inhibitor of Aurora Kinases, in Patients With Refractory Hematological Malignancies

The goal of this clinical research study is to find the highest tolerable dose of AT9283 that can be given to patients who have ALL, AML, CML, high-risk myelodysplastic syndromes, or myelofibrosis with myeloid metaplasia. Researchers want to perform pharmacokinetic (PK) testing on blood to find out how quickly the study drug leaves the body and how the body breaks down the drug. The safety and effectiveness of this drug will also be studied.

开始日期2006-09-01

申办/合作机构

Astex Pharmaceuticals, Inc.

100 项与 AT-9283 相关的临床结果

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100 项与 AT-9283 相关的转化医学

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100 项与 AT-9283 相关的专利（医药）

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47

项与 AT-9283 相关的文献（医药）

2023-09-01·iScience

Overfit deep neural network for predicting drug-target interactions

Article

作者: Xiaolin, Xiao ; Guoping, He ; Xinping, Du ; Cuancuan, Wang ; Zhen, Tian ; Cheng, Zhang ; Yanxia, Li ; Xiaozhi, Liu ; Mingyong, Liu ; Xiaofang, Ma ; Xiyun, Bian ; Hongwei, Liu ; Na, Xue ; Chunyan, Zhang ; Kuan, Wang ; Rui, Gao ; Jinkuo, Guo

Drug-target interactions (DTIs) prediction is an important step in drug discovery. As traditional biological experiments or high-throughput screening are high cost and time-consuming, many deep learning models have been developed. Overfitting must be avoided when training deep learning models. We propose a simple framework, called OverfitDTI, for DTI prediction. In OverfitDTI, a deep neural network (DNN) model is overfit to sufficiently learn the features of the chemical space of drugs and the biological space of targets. The weights of trained DNN model form an implicit representation of the nonlinear relationship between drugs and targets. Performance of OverfitDTI on three public datasets showed that the overfit DNN models fit the nonlinear relationship with high accuracy. We identified fifteen compounds that interacted with TEK, a receptor tyrosine kinase contributing to vascular homeostasis, and the predicted AT9283 and dorsomorphin were experimentally demonstrated as inhibitors of TEK in human umbilical vein endothelial cells (HUVECs).

2023-04-01·Neoplasma

The inhibition of Aurora A kinase regulates phospholipid remodeling by upregulating LPCAT1 in glioblastoma.

Article

作者: Hao, Shu-Yu ; Deng, Yu-Xuan ; Wan, Hong ; Liu, Da-Yuan ; Zhang, Zhe ; Ji, Nan ; Zhang, Shao-Dong ; Wang, Jing ; Feng, Jie ; Miao, Ya-Zhou ; Jin, Ze-Ping

Metabolic reprogramming is a common feature of glioblastoma (GBM) progression and metastasis. Altered lipid metabolism is one of the most prominent metabolic alterations in cancer. Understanding the links between phospholipid remodeling and GBM tumorigenesis may help develop new anticancer strategies and improve treatments to overcome drug resistance. We used metabolomic and transcriptomic analyses to systematically investigate metabolic and molecular changes in low-grade glioma (LGG) and GBM. We then re-established the reprogrammed metabolic flux and membrane lipid composition in GBM based on metabolomic and transcriptomic analyses. By inhibiting Aurora A kinase via RNA interference (RNAi) and inhibitor treatment, we investigated the effect of Aurora A kinase on phospholipid reprogramming LPCAT1 enzyme expression and GBM cell proliferation in vitro and in vivo. We found that GBM displayed aberrant glycerophospholipid and glycerolipid metabolism compared with LGG. Metabolic profiling indicated that fatty acid synthesis and uptake for phospholipid synthesis were significantly increased in GBM compared to LGG. The unsaturated phosphatidylcholine (PC) and phosphatidylethanolamine (PE) levels were significantly decreased in GBM compared to LGG. The expression level of LPCAT1, which is required for the synthesis of saturated PC and PE, was upregulated in GBM, and the expression of LPCAT4, which is required for the synthesis of unsaturated PC and PE, was downregulated in GBM. Notably, the inhibition of Aurora A kinase by shRNA knockdown and treatment with Aurora A kinase inhibitors such as Alisertib, AMG900, or AT9283 upregulated LPCAT1 mRNA and protein expression in vitro. In vivo, the inhibition of Aurora A kinase with Alisertib increased LPCAT1 protein expression. Phospholipid remodeling and a reduction in unsaturated membrane lipid components were found in GBM. Aurora A kinase inhibition increased LPCAT1 expression and suppressed GBM cell proliferation. The combination of Aurora kinase inhibition with LPCAT1 inhibition may exert promising synergistic effects on GBM.

2023-01-01·Intervirology

Porcine Endogenous Retrovirus Induces CXCL10 in Human Monocytes and Monocyte-Derived Primary Cells

Article

作者: Bannert, Norbert ; Al-Shehabi, Hussein

Introduction: Pigs are suitable donor species for xenotransplantation and biological materials from these animals are used for this purpose for many years. A major risk of xenotransplantation is a zoonosis by transspecies transmission of animal viruses. In this regard, porcine endogenous retroviruses (PERVs) are of paramount importance because some of them are able to infect human cells and could induce innate immune responses. Methods: Using a replication-competent polytropic PERV-A/C strain, we have analysed the induction of innate immune responses by this virus in human monocytes, monocyte-derived macrophages, and monocyte-derived dendritic cells. Results: PERV-A/C elevates the expression of the C-X-C motif chemokine 10 (CXCL10) up to 1,000-fold in human monocytes and monocyte-derived primary cells. In comparison to CXCL10, the levels of interferon-β (IFN-β) and interferon-stimulated gene 54 (ISG54) were almost unchanged. Heat-inactivated virus did not induce CXCL10 expression. Neither treatment with the reverse transcriptase inhibitors azidothymidine (AZT) and stavudine (d4T) nor treatment with the integrase inhibitor raltegravir (RAL) reduced the activation levels. Furthermore, depletion of SAM domain and HD domain-containing protein 1 (SAMHD1), a restriction factor that blocks PERV-A/C infection at the level of reverse transcription in these myeloid cells, had no significant effect on the CXCL10 induction level. These results imply that innate immune sensing leading to the strong CXCL10 response occurs at an early step of the replication process and does not require products of reverse transcription. Inhibition of Janus kinases (JAKs) by AT9283 prevented the observed CXCL10 induction by the virus, providing evidence that the JAK-STAT signalling pathway is involved in the CXCL10 response in theses myeloid cells. Conclusion: Our findings highlight PERVs as inducers of the pro-inflammatory chemokine CXCL10 and other innate immune responses in human monocytes and derived cells with potential implications in the context of xenotransplantation.

100 项与 AT-9283 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
急性淋巴细胞白血病	临床2期	美国	Astex Pharmaceuticals, Inc.	2006-09-01
急性髓性白血病	临床2期	美国	Astex Pharmaceuticals, Inc.	2006-09-01
骨髓增生异常综合征	临床2期	美国	Astex Pharmaceuticals, Inc.	2006-09-01
费城染色体阳性慢性粒细胞白血病	临床2期	美国	Astex Pharmaceuticals, Inc.	2006-09-01
多发性骨髓瘤	临床2期	加拿大	Astex Therapeutics Ltd.	-
多发性骨髓瘤	临床2期	加拿大	Astex Therapeutics Ltd.	-
多发性骨髓瘤	临床2期	-	Otsuka Holdings Co., Ltd.	-
多发性骨髓瘤	临床2期	-	Otsuka Holdings Co., Ltd.	-
原发性骨髓纤维化	临床2期	英国	Astex Therapeutics Ltd.	-
实体瘤	临床2期	英国	-	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01145989 (ASH2014) 人工标引	临床2期	多发性骨髓瘤	8	AT-9283	(窪網夢構蓋糧壓蓋膚網) = Transient neutropenia 100%，thrombocytopenia 50%，infections 3 pts 選積簾觸廠壓憲選鬱網 (觸範廠艱構願鏇憲窪積 ) 更多	不佳	2014-12-06
NCT00522990 (Pubmed \| Clin Lymphoma Myeloma Leuk)	临床1期	难治性白血病 \| 骨髓纤维化	48	AT9283	(醖範窪蓋顧願遞鹹選繭) = myocardial infarction, hypertension, cardiomyopathy, tumor lysis syndrome, pneumonia, and multiorgan failure 夢構築製範觸觸衊製憲 (窪築鹽窪壓範憲襯選糧 ) 更多	-	2014-06-01
ASCO2008	临床1期	难治性白血病	29	AT9283	(夢獵構築蓋蓋廠鹹願鑰) = 醖範壓膚醖糧鏇憲艱廠糧餘繭窪顧鹹鑰遞夢顧 (憲淵鹽齋襯觸願餘膚鏇 )	-	2008-05-20