索曲妥林(Sotrastaurin) - 药物靶点：PKC_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Sotrastaurin (USAN/INN)、Sotrastaurin acetate

+ [3]

靶点

PKC

作用机制

PKC抑制剂(蛋白激酶C抑制剂)、免疫抑制剂

治疗领域

肿瘤免疫系统疾病遗传病与畸形+ [5]

在研适应症-

非在研适应症

肾移植急性排斥反应B细胞幼淋巴细胞白血病难治性慢性淋巴细胞白血病+ [13]

原研机构

Novartis Pharma AG

在研机构-

非在研机构

Novartis Pharmaceuticals Corp.

Novartis AG

Array BioPharma, Inc.

+ [1]

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-

登录后查看时间轴

结构

分子式C25H22N6O2

InChIKeyOAVGBZOFDPFGPJ-UHFFFAOYSA-N

CAS号425637-18-9

关联

33

项与索曲妥林相关的临床试验

NCT02285244 / Withdrawn临床2期IIT

A Phase 2 Feasibility Study of Sotrastaurin for Relapsed and Refractory CLL/SLL/PLL/RT

This phase II trial studies how well sotrastaurin acetate works in treating patients with chronic lymphocytic leukemia, small lymphocytic leukemia, prolymphocytic leukemia, or Richter's transformation that has returned or that does not respond to treatment. Sotrastaurin acetate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

开始日期2015-03-12

申办/合作机构

Ohio State University Comprehensive Cancer Center

[+1]

NCT02273219 / Completed临床1期IIT

Phase Ib Trial of AEB071, a PKC Inhibitor, in Combination With BYL719, a PI3Kα Inhibitor, in Patients With Metastatic Uveal Melanoma

Primary objective is to define the maximum tolerated dose (MTD) for the combination of AEB071 and BYL719. Secondary objectives are to define the safety and tolerability of AEB071 and BYL719.

开始日期2014-11-19

申办/合作机构

Columbia University

NCT01854606 / Completed临床1期

An Open-Label, Single-arm, Phase Ib/II Study of AEB071 (a Protein Kinase C Inhibitor) and Everolimus (mTOR Inhibitor) in Patients With CD79-mutant or ABC Subtype Diffuse Large B-Cell Lymphoma

Study of the safety and efficacy of AEB071 and EVEROLIMUS in patients with CD79-mutant or ABC subtype Diffuse Large B-Cell Lymphoma.
The trial did not progress into Phase II due to the suboptimal tolerability of the combination treatment of sotrastaurin and everolimus in the Phase Ib part of the study. There were no serious safety concerns associated with this combination.

开始日期2013-12-05

申办/合作机构

Novartis Pharmaceuticals Corp.

100 项与索曲妥林相关的临床结果

登录后查看更多信息

100 项与索曲妥林相关的转化医学

登录后查看更多信息

100 项与索曲妥林相关的专利（医药）

登录后查看更多信息

113

项与索曲妥林相关的文献（医药）

2024-06-01·iScience

Hippo-PKCζ-NFκB signaling axis: A druggable modulator of chondrocyte responses to mechanical stress

Article

作者: Cai, Xiaomin ; Rodriguez, Carlos D ; Meng, Zhipeng ; Ehlen, Quinn T ; Perez, Olivia F ; Warburton, Christopher ; Kaplan, Lee ; Wu, Chenzhou ; Huang, Chun-Yuh ; Finelli, Christina ; Wang, Ying ; Ho, Lucy ; Best, Thomas M

Recent studies have implicated a crucial role of Hippo signaling in cell fate determination by biomechanical signals. Here we show that mechanical loading triggers the activation of a Hippo-PKCζ-NFκB pathway in chondrocytes, resulting in the expression of NFκB target genes associated with inflammation and matrix degradation. Mechanistically, mechanical loading activates an atypical PKC, PKCζ, which phosphorylates NFκB p65 at Serine 536, stimulating its transcriptional activation. This mechanosensitive activation of PKCζ and NFκB p65 is impeded in cells with gene deletion or chemical inhibition of Hippo core kinases LATS1/2, signifying an essential role of Hippo signaling in this mechanotransduction. A PKC inhibitor AEB-071 or PKCζ knockdown prevents p65 Serine 536 phosphorylation. Our study uncovers that the interplay of the Hippo signaling, PKCζ, and NFκB in response to mechanical loading serves as a therapeutic target for knee osteoarthritis and other conditions resulting from mechanical overloading or Hippo signaling deficiencies.

2023-10-01·Acta Pharmacologica Sinica

Loss of DJ-1 function contributes to Parkinson’s disease pathogenesis in mice via RACK1-mediated PKC activation and MAO-B upregulation

Article

作者: Zhang, Zi-Jia ; Li, Bin ; Liu, Le-le ; Kaznacheyeva, Elena ; Ren, Hai-Gang ; Han, Yu ; Guo, Dong-Kai ; Ding, Jian-Qing ; Wang, Guang-Hui ; Hu, Yu-Wei ; Wang, Yi-Qi

Parkinson's disease (PD) is a common neurodegenerative motor disorder characterized by a dramatic reduction in pars compacta of substantia nigra dopaminergic neurons and striatal dopamine (DA) levels. Mutations or deletions in the PARK7/DJ-1 gene are associated with an early-onset familial form of PD. DJ-1 protein prevents neurodegeneration via its regulation of oxidative stress and mitochondrial function as well as its roles in transcription and signal transduction. In this study, we investigated how loss of DJ-1 function affected DA degradation, ROS generation and mitochondrial dysfunction in neuronal cells. We showed that loss of DJ-1 significantly increased the expression of monoamine oxidase (MAO)-B but not MAO-A in both neuronal cells and primary astrocytes. In DJ-1-knockout (KO) mice, MAO-B protein levels in the substantia nigra (SN) and striatal regions were significantly increased. We demonstrated that the induction of MAO-B expression by DJ-1 deficiency depended on early growth response 1 (EGR1) in N2a cells. By coimmunoprecipitation omics analysis, we found that DJ-1 interacted with receptor of activated protein C kinase 1 (RACK1), a scaffolding protein, and thus inhibited the activity of the PKC/JNK/AP-1/EGR1 cascade. The PKC inhibitor sotrastaurin or the JNK inhibitor SP600125 completely inhibited DJ-1 deficiency-induced EGR1 and MAO-B expression in N2a cells. Moreover, the MAO-B inhibitor rasagiline inhibited mitochondrial ROS generation and rescued neuronal cell death caused by DJ-1 deficiency, especially in response to MPTP stimulation in vitro and in vivo. These results suggest that DJ-1 exerts neuroprotective effects by inhibiting the expression of MAO-B distributed at the mitochondrial outer membrane, which mediates DA degradation, ROS generation and mitochondrial dysfunction. This study reveals a mechanistic link between DJ-1 and MAO-B expression and contributes to understanding the crosslinks among pathogenic factors, mitochondrial dysfunction and oxidative stress in PD pathogenesis.

2023-08-01·American Journal of Physiology-Cell Physiology

Distinct protein kinase C isoforms drive the cell cycle re-entry of two separate populations of neonatal rat ventricular cardiomyocytes

Article

作者: Gagnon, Emmanuelle ; Kebbe, Mariana ; Assous, Ines ; Calderone, Angelino ; McCall, Anthony ; Villeneuve, Louis ; Naud, Patrice ; Nguyen, Quang Trinh ; Leblanc, Charles Alexandre

The appearance of nestin(+)-neonatal rat ventricular cardiomyocytes that re-entered the cell cycle following phorbol ester stimulation in the presence of p38α/β MAPK inhibitor SB203580 was associated with the inhibition of Runx1 and CDKN2a mRNA upregulation. PKC-α selectively induced the cell cycle re-entry of nestin(+)-neonatal rat ventricular cardiomyocytes. Pharmacological inhibition of PKC-α with concomitant p38α/β MAPK suppression unmasked the cell cycle re-entry of a second population of neonatal rat ventricular cardiomyocytes in the absence of nestin expression.

100 项与索曲妥林相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
D09671	-	-	DB12369

研发状态

10 条进展最快的记录,

登录

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
肾移植急性排斥反应	临床2期	捷克	Novartis Pharmaceuticals Corp.	2007-07-01
肾移植急性排斥反应	临床2期	法国	Novartis Pharmaceuticals Corp.	2007-07-01
肾移植急性排斥反应	临床2期	斯洛伐克	Novartis Pharmaceuticals Corp.	2007-07-01
肾移植急性排斥反应	临床2期	荷兰	Novartis Pharmaceuticals Corp.	2007-07-01
肾移植急性排斥反应	临床2期	比利时	Novartis Pharmaceuticals Corp.	2007-07-01
肾移植急性排斥反应	临床2期	新加坡	Novartis Pharmaceuticals Corp.	2007-07-01
肾移植急性排斥反应	临床2期	德国	Novartis Pharmaceuticals Corp.	2007-07-01
肾移植急性排斥反应	临床2期	澳大利亚	Novartis Pharmaceuticals Corp.	2007-07-01
肾移植急性排斥反应	临床2期	瑞士	Novartis Pharmaceuticals Corp.	2007-07-01
肾移植急性排斥反应	临床1期	挪威	Novartis Pharmaceuticals Corp.	2007-07-01

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01430416 (ASCO2014)	临床1期	葡萄膜黑色素瘤	118	AEB071	(糧顧願餘窪構觸築觸築) = 願鏇廠製膚願膚憲選醖衊製構夢鹹廠廠鏇選鹽 (繭襯觸蓋鏇築獵襯顧網 )	-	2014-05-20
NCT01064791 (Pubmed \| MMWR Morb Mortal Wkly Rep)	临床2期	-	298	Sotrastaurin 100 mg	鏇膚襯窪鏇糧夢淵鑰糧(獵糧構顧艱壓遞觸獵鬱) = 顧繭願鏇憲淵鹽網範選簾憲獵簾繭願鑰簾鏇築 (範鏇鹹壓鑰獵鏇鹽網膚 ) 更多	-	2013-07-01
NCT01064791 (Pubmed \| MMWR Morb Mortal Wkly Rep)	临床2期	-	298	Sotrastaurin 200 mg	鏇膚襯窪鏇糧夢淵鑰糧(獵糧構顧艱壓遞觸獵鬱) = 簾壓鏇願鑰艱憲壓壓鏇簾憲獵簾繭願鑰簾鏇築 (範鏇鹹壓鑰獵鏇鹽網膚 ) 更多	-	2013-07-01