Delving into the Latest Updates on AT-7519 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-piperidin-4-yl-1H-pyrazole-3-carboxamide

+ [3]

Target

CDK1 x CDK2 x CDK9

Mechanism

CDK1 inhibitors(Cyclin-dependent kinase 1 inhibitors), CDK2 inhibitors(Cyclin-dependent kinase 2 inhibitors), CDK9 inhibitors(Cyclin-dependent kinase 9 inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases+ [1]

Active Indication-

Inactive Indication

Mantle cell lymphoma recurrentMultiple MyelomaRecurrent Chronic Lymphoid Leukemia

Originator Organization

Astex Pharmaceuticals, Inc.

Active Organization-

Inactive Organization

Astex Pharmaceuticals, Inc.

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC16H18Cl3N5O2

InChIKeyPAOFPNGYBWGKCO-UHFFFAOYSA-N

CAS Registry902135-91-5

View All Structures (2)

This phase I trial studies the side effects and best dose of onalespib and CDKI AT7519 in treating patients with solid tumors that have spread from the primary site (place where they started) to other places in the body (metastatic) or cannot be removed by surgery. Onalespib and CDKI AT7519 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Start Date08 Apr 2016

Sponsor / Collaborator

National Cancer Institute

NCT01652144 / CompletedPhase 2IIT

A Phase II Study of AT7519M, a CDK Inhibitor, in Patients With Relapsed Mantle Cell Lymphoma

The purpose of this study is to find out what effects a new drug AT7519M has on mantle cell lymphoma.

Start Date14 Sep 2012

Sponsor / Collaborator

NCIC Clinical Trials Group

[+1]

NCT01627054 / CompletedPhase 2IIT

A Phase II Study of AT7519M, a CDK Inhibitor, in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia

The purpose of this study is to find out what effects a new drug AT7519M has on chronic lymphocytic leukemia.

Start Date27 Aug 2012

Sponsor / Collaborator

NCIC Clinical Trials Group

[+1]

100 Clinical Results associated with AT-7519

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100 Translational Medicine associated with AT-7519

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100 Patents (Medical) associated with AT-7519

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72

Literatures (Medical) associated with AT-7519

01 Jun 2024·Heliyon

Novel ferroptosis signature for improving prediction of prognosis and indicating gene targets from single-cell level in oral squamous cell carcinoma

Article

Author: Jia, Bo ; Zhao, JianJiang ; Tang, Zhengming ; Huang, Yisheng ; Chen, Yuanxin

BackgroundOral squamous cell carcinoma (OSCC) is one of the most prevalent kinds of cancers. Therefore, there is a pressing need to create a new risk scoring model to personalize the prognosis of OSCC patients and screen for patient-specific therapeutic agents and molecular targets.MethodsFirstly, A series of bioinformatics was performed to construct a novel ferroptosis-related prognostic model; Further, drug sensitivity analysis was used to screen for specific therapeutic agents for OSCC; Single-cell analysis was employed to investigate the enrichment of FRDEGs (ferroptosis-related differentially expressed genes) in the OSCC microenvironment; Finally, various experiments were conducted to screen and validate molecular therapeutic targets for OSCC.ResultsIn this study, we constructed a novel 10-FRDEGs risk scoring model. Base on the risk scoring model, we founded three potential chemotherapeutic agents for OSCC: 5Z)-7-Oxozeaenol, AT-7519, KIN001-266; In addition, FRDEGs were enriched in the epithelial cells of OSCC. Finally, we found that CA9 and CAV1 could regulate OSCC proliferation, migration and ferroptosis in vitro.ConclusionA novel 10-FRDEGs risk scoring model can predict the prognosis of patients with OSCC.Further,5Z)-7-Oxozeaenol, AT-7519, KIN001-266 are potential chemotherapeutic agents for OSCC.Moreover, we identified CA9、CAV1 as potential molecular target for the treatment of OSCC.Our findings provide new directions for prognostic assessment and precise treatment of oral cell squamous carcinoma.

01 Apr 2024·International Journal of Biological Macromolecules

An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase

Article

Author: Zhang, Yunju ; Liu, Yang ; Li, Yong-Qiang ; Guo, Jingjing ; Li, Weifeng ; Qu, Yuanyuan ; Mu, Yuguang

The main proteinase (M^pro) of SARS-CoV-2 plays a critical role in cleaving viral polyproteins into functional proteins required for viral replication and assembly, making it a prime drug target for COVID-19. It is well known that noncompetitive inhibition offers potential therapeutic options for treating COVID-19, which can effectively reduce the likelihood of cross-reactivity with other proteins and increase the selectivity of the drug. Therefore, the discovery of allosteric sites of M^pro has both scientific and practical significance. In this study, we explored the binding characteristics and inhibiting process of M^pro activity by two recently reported allosteric inhibitors, pelitinib and AT7519 which were obtained by the X-ray screening experiments, to probe the allosteric mechanism via molecular dynamic (MD) simulations. We found that pelitinib and AT7519 can stably bind to M^pro far from the active site. The binding affinity is estimated to be -24.37 ± 4.14 and - 26.96 ± 4.05 kcal/mol for pelitinib and AT7519, respectively, which is considerably stable compared with orthosteric drugs. Furthermore, the strong binding caused clear changes in the catalytic site of M^pro, thus decreasing the substrate accessibility. The community network analysis also validated that pelitinib and AT7519 strengthened intra- and inter-domain communication of M^pro dimer, resulting in a rigid M^pro, which could negatively impact substrate binding. In summary, our findings provide the detailed working mechanism for the two experimentally observed allosteric sites of M^pro. These allosteric sites greatly enhance the 'druggability' of M^pro and represent attractive targets for the development of new M^pro inhibitors.

19 Jan 2024·ACS Chemical Biology

Degradation by Design: New Cyclin K Degraders from Old CDK Inhibitors

Article

Author: Choudhary, Jyoti S ; Bouguenina, Habib ; Rossanese, Olivia W ; Sialana, Fernando J ; Hayhow, Thomas G ; Bellenie, Benjamin R ; Thomas, Katie L ; Miller, Daniel S J

Small molecules that induce protein degradation hold the potential to overcome several limitations of the currently available inhibitors. Monovalent or molecular glue degraders, in particular, enable the benefits of protein degradation without the disadvantages of high molecular weight and the resulting challenge in drug development that are associated with bivalent molecules like Proteolysis Targeting Chimeras. One key challenge in designing monovalent degraders is how to build in the degrader activity─how can we convert an inhibitor into a degrader? If degradation activity requires very specific molecular features, it will be difficult to find new degraders and challenging to optimize those degraders toward drugs. Herein, we demonstrate that an unexpectedly wide range of modifications to the degradation-inducing group of the cyclin K degrader CR8 are tolerated, including both aromatic and nonaromatic groups. We used these findings to convert the pan-CDK inhibitors dinaciclib and AT-7519 to Cyclin K degraders, leading to a novel dinaciclib-based compound with improved degradation activity compared to CR8 and confirm the mechanism of degradation. These results suggest that general design principles can be generated for the development and optimization of monovalent degraders.

100 Deals associated with AT-7519

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB08142

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Mantle cell lymphoma recurrent	Phase 2	CA	Astex Pharmaceuticals, Inc.	14 Sep 2012
Recurrent Chronic Lymphoid Leukemia	Phase 2	CA	Astex Pharmaceuticals, Inc.	27 Aug 2012
Multiple Myeloma	Phase 2	US	Astex Pharmaceuticals, Inc.	01 Nov 2010

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02503709 (Pubmed) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	28	onalespib+AT7519	(mwceeqjmfx) = onalespib 80 mg/m2 IV + AT7519 21 mg/m2 IV vbggsxckvi (eizeqrfkoc ) View more	Positive	01 Dec 2020
NCT01627054 \| NCT01652144 (Pubmed \| Leukemia) Manual	Phase 2	Mantle-Cell Lymphoma \| Chronic Lymphocytic Leukemia	19	AT7519M (CLL patients)	(ohwyrcymdx) = bfhjahacdt mjptaopgns (pgjrjrsqts )	Negative	01 Jun 2017
NCT01627054 \| NCT01652144 (Pubmed \| Leukemia) Manual	Phase 2	Mantle-Cell Lymphoma \| Chronic Lymphocytic Leukemia	19	AT7519M (MCL patients)	(rjkoayuybx) = wyvitxfvgg ikkvlvzokd (ovobkwspib ) View more	Negative	01 Jun 2017
NCT00390117 (NCIC Clinical Trials Group IND 177, Pubmed \| Med J Aust)	Phase 1	Advanced cancer	34	AT7519	vzudiysuwn(moqvlefnkg) = There was no clinically significant QTc prolongation rwowmerjgr (nzitfbrmow ) View more	-	09 Dec 2014