Delving into the Latest Updates on AT-9283 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

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

Mechanism

Aurora A inhibitors(Serine/threonine-protein kinase Aurora-A inhibitors), Aurora B inhibitors(Serine/threonine-protein kinase Aurora-B inhibitors), Bcr-Abl T315I inhibitors(BCR-ABL T315I mutation inhibitors)

+ [2]

Therapeutic Areas

NeoplasmsImmune System DiseasesCardiovascular Diseases+ [3]

Active Indication-

Inactive Indication

acute leukemiaAcute Lymphoblastic LeukemiaAcute Myeloid Leukemia+ [7]

Originator Organization

Astex Therapeutics Ltd.

Active Organization-

Inactive Organization

Astex Pharmaceuticals, Inc.

Astex Therapeutics Ltd.

Cancer Research UK

+ [1]

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC19H24ClN7O2

InChIKeyNHFNYIVVGIXBPD-UHFFFAOYSA-N

CAS Registry896466-61-8

View All Structures (2)

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.

Start Date01 Sep 2006

Sponsor / Collaborator

Astex Pharmaceuticals, Inc.

100 Clinical Results associated with AT-9283

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100 Translational Medicine associated with AT-9283

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100 Patents (Medical) associated with AT-9283

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47

Literatures (Medical) associated with AT-9283

01 Sep 2023·iScience

Overfit deep neural network for predicting drug-target interactions

Article

Author: 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).

01 Apr 2023·Neoplasma

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

Article

Author: 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.

01 Jan 2023·Intervirology

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

Article

Author: 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 Deals associated with AT-9283

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Lymphoblastic Leukemia	Phase 2	US	Astex Pharmaceuticals, Inc.	01 Sep 2006
Acute Myeloid Leukemia	Phase 2	US	Astex Pharmaceuticals, Inc.	01 Sep 2006
Myelodysplastic Syndromes	Phase 2	US	Astex Pharmaceuticals, Inc.	01 Sep 2006
Philadelphia chromosome positive chronic myelogenous leukemia	Phase 2	US	Astex Pharmaceuticals, Inc.	01 Sep 2006
Multiple Myeloma	Phase 2	CA	Astex Therapeutics Ltd.	-
Multiple Myeloma	Phase 2	CA	Astex Therapeutics Ltd.	-
Multiple Myeloma	Phase 2	-	Otsuka Holdings Co., Ltd.	-
Multiple Myeloma	Phase 2	-	Otsuka Holdings Co., Ltd.	-
Primary Myelofibrosis	Phase 2	GB	Astex Therapeutics Ltd.	-
Solid tumor	Phase 2	GB	-	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01145989 (ASH2014) Manual	Phase 2	Multiple Myeloma	8	AT-9283	(lufpqeguvx) = Transient neutropenia 100%，thrombocytopenia 50%，infections 3 pts tsvvcwwtng (owebnoddyf ) View more	Negative	06 Dec 2014
NCT00522990 (Pubmed \| Clin Lymphoma Myeloma Leuk)	Phase 1	Refractory Leukemia \| Myelofibrosis	48	AT9283	(bpjxoaxgju) = myocardial infarction, hypertension, cardiomyopathy, tumor lysis syndrome, pneumonia, and multiorgan failure epgvifcmnx (yygzghjvgb ) View more	-	01 Jun 2014
ASCO2008	Phase 1	Refractory Leukemia	29	AT9283	(hooqblogwe) = pzqwyoufhm kmulpddruh (ousbwxnnea )	-	20 May 2008