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

Action

inhibitors

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 DiseasesHemic and Lymphatic Diseases+ [2]

Active Indication-

Inactive Indication

acute leukemiaAcute Lymphoblastic LeukemiaAcute Myeloid Leukemia+ [10]

Originator Organization

Astex Therapeutics Ltd.

Active Organization-

Inactive Organization

Astex Pharmaceuticals, Inc.

Cancer Research UK

Astex Therapeutics Ltd.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

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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134

Literatures (Medical) associated with AT-9283

05 Jul 2024·Oncogene

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

Article

Author: 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.

27 Jun 2024·Journal of Medicinal Chemistry

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

Article

Author: 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.

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).

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
Refractory Multiple Myeloma	Phase 2	Canada	Astex Pharmaceuticals, Inc.	15 Feb 2011
Relapse multiple myeloma	Phase 2	Canada	Astex Pharmaceuticals, Inc.	15 Feb 2011
Acute Lymphoblastic Leukemia	Phase 2	United States	Astex Pharmaceuticals, Inc.	01 Sep 2006
Acute Myeloid Leukemia	Phase 2	United States	Astex Pharmaceuticals, Inc.	01 Sep 2006
Chronic phase chronic myeloid leukemia	Phase 2	United States	Astex Pharmaceuticals, Inc.	01 Sep 2006
Myelodysplastic Syndromes	Phase 2	United States	Astex Pharmaceuticals, Inc.	01 Sep 2006
Myelofibrosis	Phase 2	United States	Astex Pharmaceuticals, Inc.	01 Sep 2006
Philadelphia chromosome positive chronic myelogenous leukemia	Phase 2	United States	Astex Pharmaceuticals, Inc.	01 Sep 2006
Primary Myelofibrosis	Phase 2	United Kingdom	Astex Therapeutics Ltd.	-
Solid tumor	Phase 2	Canada	-	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ATPS-20 (SNO2015)	Not Applicable	Glioblastoma Aurora kinase A \| Aurora kinase B	-	AT9283	tkcsykodrn(hmcwsimzcj) = a consequence of mitotic defects tzjfcdikpv (ukxubvmzfm )	-	09 Nov 2015
NCT01145989 (ASH 12014 \| ASH 22014) Manual	Phase 2	Multiple Myeloma	8	AT-9283	(iuypecduaa) = Transient neutropenia 100%，thrombocytopenia 50%，infections 3 pts zsdhibrlhy (jpaczwkwkv ) View more	Negative	06 Dec 2014
NCT00522990 (Pubmed \| Clin Lymphoma Myeloma Leuk)	Phase 1	Refractory Leukemia \| Myelofibrosis	48	AT9283	(rrbidutigx) = myocardial infarction, hypertension, cardiomyopathy, tumor lysis syndrome, pneumonia, and multiorgan failure qzohmdfcoi (jlodmshiyo ) View more	-	01 Jun 2014
ASCO2008	Phase 1	Refractory Leukemia	29	AT9283	(lljjgkhlnk) = tyyprlneyx wbwbfvnefy (jnxexwjmiy )	-	20 May 2008