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

作用方式

抑制剂

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

肿瘤免疫系统疾病血液及淋巴系统疾病+ [2]

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+ [10]

原研机构

Astex Therapeutics Ltd.

在研机构-

非在研机构

Astex Pharmaceuticals, Inc.

Cancer Research UK

Astex Therapeutics Ltd.

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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134

项与 AT-9283 相关的文献（医药）

2024-07-05·Oncogene

Targeting AURKA to induce synthetic lethality in CREBBP-deficient B-cell malignancies via attenuation of MYC expression

Article

作者: Wang, Peili ; Ong, Choon Kiat ; Lim, Soon Thye ; Yu, Qiang ; Chan, Jason Yongsheng ; Sun, Yichen ; Liu, Lizhen ; Hong, Jing Han ; Xu, Banglao ; Wang, Yali ; Yu, Zhaoliang ; Li, Wenyu ; Pan, Lu ; Deng, Peng ; Xiao, Rong ; Liu, Shini ; Gao, Jiuping ; Teng, Yan ; Chen, Jianfeng ; Teh, Bin Tean ; Tan, Jing ; Chai, Kelila Xin Ye

Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in B-cell malignancies, highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk B-cell malignancies harboring CREBBP inactivating mutations.

2024-06-27·Journal of Medicinal Chemistry

Functional and Structural Characterization of Clinical-Stage Janus Kinase 2 Inhibitors Identifies Determinants for Drug Selectivity

Article

作者: Silvennoinen, Olli ; Skoda, Radek C ; Zmajkovic, Jakub ; Miao, Ya ; Hilpert, Morgane ; Virtanen, Anniina ; Haikarainen, Teemu

Janus kinase 2 (JAK2) plays a critical role in orchestrating hematopoiesis, and its deregulation leads to various blood disorders, most importantly myeloproliferative neoplasms (MPNs). Ruxolitinib, fedratinib, momelotinib, and pacritinib are FDA-/EMA-approved JAK inhibitors effective in relieving symptoms in MPN patients but show variable clinical profiles due to poor JAK selectivity. The development of next-generation JAK2 inhibitors is hampered by the lack of comparative functional analysis and knowledge of the molecular basis of their selectivity. Here, we provide mechanistic profiling of the four approved and six clinical-stage JAK2 inhibitors and connect selectivity data with high-resolution structural and thermodynamic analyses. All of the JAK inhibitors potently inhibited JAK2 activity. Inhibitors differed in their JAK isoform selectivity and potency for erythropoietin signaling, but their general cytokine inhibition signatures in blood cells were comparable. Structural data indicate that high potency and moderate JAK2 selectivity can be obtained by targeting the front pocket of the adenosine 5'-triphosphate-binding site.

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).

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
难治性多发性骨髓瘤	临床2期	加拿大	Astex Pharmaceuticals, Inc.	2011-02-15
复发性多发性骨髓瘤	临床2期	加拿大	Astex Pharmaceuticals, Inc.	2011-02-15
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
慢性期慢性髓性白血病	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
骨髓纤维化	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
原发性骨髓纤维化	临床2期	英国	Astex Therapeutics Ltd.	-
实体瘤	临床2期	加拿大	-	-

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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


ATPS-20 (SNO2015)	N/A	胶质母细胞瘤 Aurora kinase A \| Aurora kinase B	-	AT9283	膚襯遞範鬱壓選糧艱齋(蓋淵夢鹽齋鑰顧衊廠網) = a consequence of mitotic defects 憲鏇獵醖壓積製艱願構 (鏇夢鹽餘餘觸襯鏇窪鬱 )	-	2015-11-09
NCT01145989 (ASH 12014 \| ASH 22014) 人工标引	临床2期	多发性骨髓瘤	8	AT-9283	(遞襯遞製願顧糧顧蓋蓋) = Transient neutropenia 100%，thrombocytopenia 50%，infections 3 pts 衊醖廠積選窪顧淵觸鹹 (鏇淵衊鹽廠獵艱襯齋鏇 ) 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	(齋鑰鏇範憲糧膚網糧蓋) = myocardial infarction, hypertension, cardiomyopathy, tumor lysis syndrome, pneumonia, and multiorgan failure 廠築艱觸製壓醖壓製構 (餘網繭鏇築壓膚蓋夢鬱 ) 更多	-	2014-06-01
ASCO2008	临床1期	难治性白血病	29	AT9283	(醖鬱淵襯鹹獵製壓蓋製) = 壓膚鹹膚壓淵鏇積鬱醖齋窪衊獵餘廠遞醖衊鑰 (製窪艱膚顧網選膚醖鹹 )	-	2008-05-20