Delving into the Latest Updates on AZD-1480 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

JAK1 x JAK2

Mechanism

JAK1 inhibitors(Tyrosine-protein kinase JAK1 inhibitors), JAK2 inhibitors(Tyrosine-protein kinase JAK2 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersHemic and Lymphatic Diseases+ [2]

Active Indication-

Inactive Indication

Advanced Hepatocellular CarcinomaAdvanced Malignant Solid NeoplasmHepatocellular Carcinoma+ [8]

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization-

Inactive Organization

AstraZeneca PLC

AstraZeneca Pharmaceuticals Co. Ltd.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC14H14ClFN8

InChIKeyPDOQBOJDRPLBQU-QMMMGPOBSA-N

CAS Registry935666-88-9

A Phase I, Open-label, Multicentre, Dose Escalation Study to Assess the Safety and Tolerability, and Pharmacokinetics of AZD1480 in Asian Patients With Advanced Solid Malignancies and Asian Patients With Child-Pugh A to B7 Advanced Hepatocellular Carcinoma (HCC) in the Escalation Phase, Estimated Glomerular Filtration Rate(EGFR) or ROS Mutant NSCLC and Non-smokers With Lung Metastasis and Gastric Cancer and Solid Tumour With Biopsy Available in the Expansion Phase.

This is Phase I, open-label and dose escalation study to evaluate the safety and tolerability of AZD1480(JAK2 inhibitor) in Asian patients with advanced solid tumors (Part A and C) and in patients with advanced HCC (Part B) in the escalation phase, EGFR or ROS mutant NSCLC and non-smokers with lung metastasis and gastric cancer in the expansion phase and to evaluate daily and BID dosing.

Start Date01 Nov 2010

Sponsor / Collaborator

AstraZeneca PLC

NCT01112397 / TerminatedPhase 1

A Phase I, Open-Label, Multi-Center, Dose-Escalation Study to Assess the Safety and Tolerability, and Pharmacokinetics of AZD1480 Administered as Daily Oral Monotherapy in Patients With Advanced Solid Malignancies in the Escalation Phase and EGFR or ROS Mutant NSCLC or Non-Smokers With Lung Metastasis in the Expansion Phase.

This study is being conducted to assess the safety, tolerability and PK of AZD1480 in patients with advanced solid malignancies.

Start Date01 Apr 2010

Sponsor / Collaborator

AstraZeneca PLC

NCT00910728 / CompletedPhase 1

A PhaseI/II, Open Label Multi-Centre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the JAK2 Inhibitor AZD1480 Administered Orally to Patients With Primary Myelofibrosis (PMF) and Post-Polycythaemia Vera/Essential Thrombocythaemia Myelofibrosis (Post-PV/ET MF

This study is being conducted to test study drug AZD1480 to see how it may work to treat myeloproliferative diseases. The main purpose of this study is to determine the safety and tolerability of AZD1480. This is the first time the drug has been given to humans and is classed as a first time in man study. Its main purpose is to establish a safe dosage of the drug and provide additional information on any potential side effects this drug may cause. The study will also assess the blood levels and action of AZD1480 in the body over a period of time and will indicate whether the drug has a therapeutic effect on myeloproliferative diseases.

Start Date01 May 2009

Sponsor / Collaborator

AstraZeneca PLC

[+1]

100 Clinical Results associated with AZD-1480

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100 Translational Medicine associated with AZD-1480

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100 Patents (Medical) associated with AZD-1480

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88

Literatures (Medical) associated with AZD-1480

04 Sep 2024·Biochemical Journal

Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation

Article

Author: Meng, Yanxiang ; Hildebrand, Joanne M. ; Young, Samuel N. ; Garnish, Sarah E. ; Murphy, James M. ; Horne, Christopher R. ; Jacobsen, Annette V.

Necroptosis is a lytic and pro-inflammatory form of programmed cell death executed by the terminal effector, the MLKL (mixed lineage kinase domain-like) pseudokinase. Downstream of death and Toll-like receptor stimulation, MLKL is trafficked to the plasma membrane via the Golgi-, actin- and microtubule-machinery, where activated MLKL accumulates until a critical lytic threshold is exceeded and cell death ensues. Mechanistically, MLKL's lytic function relies on disengagement of the N-terminal membrane-permeabilising four-helix bundle domain from the central autoinhibitory brace helix: a process that can be experimentally mimicked by introducing the R30E MLKL mutation to induce stimulus-independent cell death. Here, we screened a library of 429 kinase inhibitors for their capacity to block R30E MLKL-mediated cell death, to identify co-effectors in the terminal steps of necroptotic signalling. We identified 13 compounds — ABT-578, AR-A014418, AZD1480, AZD5363, Idelalisib, Ipatasertib, LJI308, PHA-793887, Rapamycin, Ridaforolimus, SMI-4a, Temsirolimus and Tideglusib — each of which inhibits mammalian target of rapamycin (mTOR) signalling or regulators thereof, and blocked constitutive cell death executed by R30E MLKL. Our study implicates mTOR signalling as an auxiliary factor in promoting the transport of activated MLKL oligomers to the plasma membrane, where they accumulate into hotspots that permeabilise the lipid bilayer to cause cell death.

15 Aug 2024·Heliyon

Zhiqiao Gancao decoction regulated JAK2/STAT3/ macrophage M1 polarization to ameliorate intervertebral disc degeneration.

Article

Author: Li, Yuwei ; Zhang, Long ; Shen, Xiaofeng ; Xu, Bo ; Liu, Yujiang ; Lu, Binjie ; Chen, Hua ; Huang, Zeling ; Zhu, Zaishi

BackgroundZhiqiao Gancao decoction (ZQGCD) was created by Professor Gong Zhengfeng, a renowned Chinese medicine expert. Clinical studies have shown its efficacy in alleviating pain and enhancing lumbar function in intervertebral disc degeneration (IDD) patients. However, the precise mechanism of ZQGCD in treating IDD remains unclear.MethodsThe active components of ZQGCD were identified using Liquid chromatography-tandem mass spectrometry (LC-MS/MS). A rat model of intervertebral disc degeneration was established, and rats in each group received ZQGCD for three weeks. Assessment parameters included hyperalgesia status, observation of intervertebral disc tissue degeneration and macrophage infiltration, and analysis of JAK2/STAT3 pathway protein expression in the intervertebral disc. Primary macrophage M1 polarization was induced using LPS, with cells treated using the JAK2 inhibitor (AZD1480) and ZQGCD to evaluate macrophage polarization, cellular supernatant inflammatory factors, and JAK2/STAT3 pathway expression. Macrophage supernatant served as a conditioned medium to observe its effects on the proliferation of nucleus pulposus cells (NPCs) and the expression of collagen II and MMP3 proteins.ResultsA total of 81 active components were identified in ZQGCD. Following ZQGCD treatment, infiltrating macrophages in intervertebral disc tissues of model rats decreased, the content of M1 macrophages decreased, while the content of M2 macrophages increased, the expression of proinflammatory factors and pain-inducing factors in serum decreased, and the expression of substance P in intervertebral disc tissue decreased. Consequently, the intervertebral disc degeneration and hyperalgesia of rats were improved. In vitro studies revealed that LPS induced M1 macrophage polarization. By inhibiting the JAK2/STAT3 pathway, both JAK2 inhibitors and ZQGCD effectively suppressed M1 polarization, resulting in decreased levels of IL-1β, IL-6, TNF-α, and various other inflammatory factors. Consequently, this inhibition led to a delay in the degeneration of NPCs.ConclusionThere is macrophage infiltration in the intervertebral disc tissue of IDD rats, and JAK2/STAT3 pathway is activated, macrophages are polarized to M1 type, resulting in inflammatory microenvironment, leading to intervertebral disc degeneration and hyperalgesia. ZQGCD exhibited a delaying effect on IDD and improved hyperalgesia by inhibiting the JAK2/STAT3/macrophage M1 polarization pathway.

01 Jun 2024·Journal of Neuroimmunology

V-set and immunoglobulin domain containing 4 inhibits oxidative stress, mitochondrial dysfunction, and inflammation to attenuate Parkinson's disease progression by activating the JAK2/STAT3 pathway

Article

Author: Yin, Xinxin ; Zhuang, Jingcong ; He, Shengquan ; Xu, Jiangtao ; Cai, Pingping ; Wang, Junmei ; Zhang, Min

OBJECTIVEV-set and immunoglobulin domain containing 4 (VSIG4) inhibits neurological dysfunction, microglial M1 polarization, and inflammation to participate in the progression of neurological disorders, but evidence regarding Parkinson's disease (PD) is scarce. The present study intended to investigate the engagement of VSIG4 in PD progression, and the potential mechanism.METHODSBV-2 cells were treated with 1-Methyl-4-phenylpyridinium (MPP⁺) to establish PD model. MPP⁺ treated BV-2 cells were infected with VSIG4 overexpression adenovirus-associated virus (AAV) (oeVSIG4) and negative control AAV (oeNC), and AZD1480 (JAK2 inhibitor) was added to these cells.RESULTSMPP⁺ reduced VSIG4 mRNA (P < 0.05) and protein (P < 0.05) in BV-2 cells. Interestingly, VSIG4 reduced malondialdehyde (P < 0.01), reactive oxygen species (P < 0.01), NOD-like receptor family pyrin domain containing 3 (P < 0.05), cleaved-caspase1 (P < 0.05), tumor necrosis factor-α (P < 0.05), and interleukin-1β (P < 0.05), but increased glutathione (P < 0.05), mitochondrial membrane potential (P < 0.05), phosphorylation (p)-JAK2 (P < 0.05), and p-STAT3 (P < 0.01) in MPP⁺ treated BV-2 cells, which indicated that VSIG4 inhibited oxidative stress, mitochondrial dysfunction, and inflammation, as well as activated the JAK2/STAT3 pathway in PD model. Moreover, AZD1480 inhibited the JAK2/STAT3 pathway and aggravated oxidative stress, mitochondrial dysfunction, and inflammation in PD model (all P < 0.05). Importantly, AZD1480 attenuated the influence of VSIG4 on oxidative stress, mitochondrial dysfunction, inflammation, and the JAK2/STAT3 pathway in PD model (all P < 0.05).CONCLUSIONVSIG4 suppresses oxidative stress, mitochondrial dysfunction, and inflammation by activating the JAK2/STAT3 pathway, which may be helpful in attenuating PD progression.

100 Deals associated with AZD-1480

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External Link

KEGG	Wiki	ATC	Drug Bank
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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Myelodysplastic-Myeloproliferative Diseases	Phase 2	US	AstraZeneca PLC	01 May 2009
Myelodysplastic-Myeloproliferative Diseases	Phase 2	FR	AstraZeneca PLC	01 May 2009
Polycythemia Vera	Phase 2	US	AstraZeneca PLC	01 May 2009
Polycythemia Vera	Phase 2	FR	AstraZeneca PLC	01 May 2009
Thrombocythemia, Essential	Phase 2	US	AstraZeneca PLC	01 May 2009
Hepatocellular Carcinoma	Phase 2	-	AstraZeneca Pharmaceuticals Co. Ltd.	-
Myeloproliferative Disorders	Phase 2	FR	AstraZeneca PLC	-
Myeloproliferative Disorders	Phase 2	US	AstraZeneca PLC	-
Primary Myelofibrosis	Phase 2	-	AstraZeneca Pharmaceuticals Co. Ltd.	-
Primary Myelofibrosis	Phase 2	-	AstraZeneca Pharmaceuticals Co. Ltd.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00910728 (CTgov)	Phase 1	Polycythemia Vera \| Myelodysplastic-Myeloproliferative Diseases \| Thrombocythemia, Essential \| Primary Myelofibrosis	65	AZD1480 (2.5 mg QD)	tjlypmhlju(lvdoathjur) = jycdelpyui ljsapxbnpj (uqhifrryhm, kjjedhlaxn - shmpvogrzh) View more	-	24 Apr 2017
NCT00910728 (CTgov)	Phase 1		65	AZD1480 (5.0 mg QD)	tjlypmhlju(lvdoathjur) = pthzsjvuwq ljsapxbnpj (uqhifrryhm, qwmhiofaxk - ggexdoyhxj) View more	-	24 Apr 2017
AACR2012	Phase 2	Neoplasms \| Neuroblastoma	-	AZD1480	nnlptyaxbh(howkzokkoa) = gbmycdvwoc xuinaiehir (mgrrfdaeak )	-	15 Apr 2012