VTP-195183(VTP-195183) - 药物靶点：RARα_专利_临床

概要

基本信息

药物类型

小分子化药

别名

+ [4]

靶点

RARα

作用机制

RARα激动剂(维甲酸受体α激动剂)

治疗领域

肿瘤血液及淋巴系统疾病皮肤和肌肉骨骼疾病+ [3]

在研适应症-

非在研适应症

急性早幼粒细胞白血病乳腺癌慢性粒单核细胞白血病+ [7]

原研机构

Allergan Ltd. (Ireland)

在研机构-

非在研机构

Io Therapeutics, Inc.The Sidney Kimmel Comprehensive Cancer CenterAllergan Specialty Therapeutics, Inc.

+ [2]

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-

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结构

分子式C22H22ClF2NO4

InChIKeyPNAWUIKCVQSLFG-UHFFFAOYSA-N

CAS号367273-07-2

关联

4

项与 VTP-195183 相关的临床试验

NCT02749708 / Terminated临床1期IIT

Phase I/II Study of IRX5183 in Relapsed and Refractory Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MDS)

The purpose of this study is to evaluate the use of IRX5183 in 1) patients with relapsed and/or refractory AML and 2) patients with high-risk MDS or chronic myelomonocytic leukemia (CMML).

开始日期2017-01-30

申办/合作机构

The Sidney Kimmel Comprehensive Cancer Center

[+1]

NCT00670150 / Withdrawn临床2期IIT

Phase II Study of NRX 195183 Induction and NRX 195183 Combined With Arsenic Trioxide (As2o3) as Initial Consolidation Therapy Followed by Continuous NRX 195183 Maintenance Therapy for Patients With Untreated Acute Promyelocytic Leukemia

The safety and efficacy of combining NRX 195183 with arsenic trioxide in treating untreated APL will be assessed.

开始日期2010-05-01

申办/合作机构

University of Southern California

[+1]

NCT00675870 / Unknown status临床2期

Phase II Study of NRX 195183 Therapy for Patients With Relapsed or Refractory Acute Promyelocytic Leukemia

The purpose of this study is to determine whether NRX 195183 is effective in the treatment of relapsed or refractory Acute Promyelocytic Leukemia

开始日期2008-04-01

申办/合作机构

NuRx Pharmaceuticals, Inc.

100 项与 VTP-195183 相关的临床结果

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100 项与 VTP-195183 相关的转化医学

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100 项与 VTP-195183 相关的专利（医药）

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6

项与 VTP-195183 相关的文献（医药）

2017-02-01·Archivum Immunologiae et Therapiae Experimentalis4区 · 医学

Antagonizing Retinoic Acid Receptors Increases Myeloid Cell Production by Cultured Human Hematopoietic Stem Cells

4区 · 医学

Article

作者: Brown, Geoffrey ; Marcinkowska, Ewa ; Marchwicka, Aleksandra ; Cunningham, Alan ; Toellner, Kai-Michael

Activities of the retinoic acid receptor (RAR)α and RARγ are important to hematopoiesis. Here, we have investigated the effects of receptor selective agonists and antagonists on the primitive human hematopoietic cell lines KG1 and NB-4 and purified normal human hematopoietic stem cells (HSCs). Agonizing RARα (by AGN195183) was effective in driving neutrophil differentiation of NB-4 cells and this agonist synergized with a low amount (10 nM) of 1α,25-dihydroxyvitamin D₃ to drive monocyte differentiation of NB-4 and KG1 cells. Treatment of cultures of human HSCs (supplemented with stem cell factor ± interleukin 3) with an antagonist of all RARs (AGN194310) or of RARα (AGN196996) prolonged the lifespan of cultures, up to 55 days, and increased the production of neutrophils and monocytes. Slowing down of cell differentiation was not observed, and instead, hematopoietic stem and progenitor cells had expanded in number. Antagonism of RARγ (by AGN205728) did not affect cultures of HSCs. Studies of CV-1 and LNCaP cells transfected with RAR expression vectors and a reporter vector revealed that RARγ and RARβ are activated by sub-nM all-trans retinoic acid (EC₅₀-0.3 nM): ~50-fold more is required for activation of RARα (EC₅₀-16 nM). These findings further support the notion that the balance of expression and activity of RARα and RARγ are important to hematopoietic stem and progenitor cell expansion and differentiation.

2013-06-01·Leukemia1区 · 医学

ATRA and the specific RARα agonist, NRX195183, have opposing effects on the clonogenicity of pre-leukemic murine AML1-ETO bone marrow cells

1区 · 医学

Article

作者: L C Y Chee ; G A McArthur ; L E Purton ; J Hendy

All-trans retinoic acid (ATRA) is used successfully in the treatment of acute promyelocytic leukemia (APL). ATRA enhances hematopoietic stem cell self-renewal through retinoic acid receptor (RAR)γ activation while promoting differentiation of committed myeloid progenitors through RARα activation. Its lack of success in the treatment of non-APL acute myeloid leukemia (AML) may be related to ATRA's non-selectivity for the RARα and RARγ isotypes, and specific RARα activation may be more beneficial in promoting myeloid differentiation. To investigate this hypothesis, the effects of ATRA and the specific RARα agonist NRX195183 was assessed in AML1-ETO (AE)-expressing murine bone marrow (BM) progenitors. ATRA potentiated the in vitro clonogenicity of these cells while NRX195183 had the opposite effect. Morphological and flow cytometric analysis confirmed a predominantly immature myeloid population in the ATRA-treated AE cells while the NRX195183-treated cells demonstrated an increase in the mature myeloid population. Similarly, NRX195183 treatment promoted myeloid differentiation in an AE9a in vivo murine model. In the ATRA-treated AE cells, gene expression analyses revealed functional networks involving SERPINE1 and bone morphogenetic protein 2; AKT phosphorylation was upregulated. Collectively, these findings confirm the contrasting roles of specific RARα and RARγ activation in the clonogenicity and differentiation of AE cells with potential significant implications in the treatment of non-APL AML using a specific RARα agonist.

2010-02-01·Journal of Orthopaedic Research3区 · 医学

Inhibition of ectopic bone formation by a selective retinoic acid receptor α‐agonist: A new therapy for heterotopic ossification?

3区 · 医学

Article

作者: Masahiro Iwamoto ; Tiffany N. Morrison ; Kengo Shimono ; Julie A. Williams ; Wei-en Tung ; Maurizio Pacifici ; Roshantha A. Chandraratna

AbstractHeterotopic ossification (HO) consists of formation of ectopic cartilage followed by endochondral bone and is triggered by major surgeries, large wounds, and other conditions. Current therapies, including low‐dose irradiation, are not always effective and do not target the skeletogenic process directly. Because chondrogenesis requires a decrease of nuclear retinoic acid receptor α (RARα) action, we reasoned that pharmacologic activation of this receptor pathway should inhibit HO. Thus, we selected the synthetic retinoid NRX195183, a potent and highly selective RARα‐agonist, and found that it did inhibit chondrogenesis in mouse limb micromass cultures. We established a mouse HO model consisting of subcutaneous implantation of Matrigel mixed with rhBMP‐2. Control mice receiving daily oral doses of vehicle (peanut oil) or retinol (a natural nonactive retinoid precursor) developed large HO‐like masses by days 9–12 that displayed abundant cartilage, endochondral bone, vessels, and marrow. In contrast, formation of HO‐like masses was markedly reduced in companion mice receiving daily oral doses of α‐agonist. These ectopic masses contained sharply reduced amounts of cartilage and bone, blood vessels, and TRAP‐positive osteoclasts, and expressed markedly lower levels of master chondrogenic genes including Sox9, cartilage genes such as collagen XI and X, and osteogenic genes including Runx2. The data provide proof‐of‐principle evidence that a pharmacological strategy involving a selective RARα‐agonist can indeed counteract an ectopic skeletal‐formation process effectively and efficiently, and could thus represent a novel preventive treatment for HO. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:271–277, 2010

100 项与 VTP-195183 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05653

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
慢性粒单核细胞白血病	临床3期	美国	The Sidney Kimmel Comprehensive Cancer Center	2017-01-30
慢性粒单核细胞白血病	临床2期	美国	Io Therapeutics, Inc.	2017-01-30
骨髓增生异常综合征	临床2期	美国	The Sidney Kimmel Comprehensive Cancer Center	2017-01-30
骨髓增生异常综合征	临床2期	美国	Io Therapeutics, Inc.	2017-01-30
难治性急性髓细胞白血病	临床2期	美国	Io Therapeutics, Inc.	2017-01-30
难治性急性髓细胞白血病	临床2期	美国	The Sidney Kimmel Comprehensive Cancer Center	2017-01-30
急性早幼粒细胞白血病	临床2期	美国	NuRx Pharmaceuticals, Inc.	2008-04-01
中性粒细胞减少	临床2期	澳大利亚	Vitae Pharmaceuticals LLC	2005-10-15
乳腺癌	临床2期	美国	Allergan Specialty Therapeutics, Inc.	2002-11-13
干细胞动员	临床2期	澳大利亚	-	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02749708 (Pubmed \| Front Oncol) 人工标引	临床1期	急性髓性白血病	11	IRX 5183	(淵淵願鏇積繭繭鹹遞範) = cAE included hypertriglyceridemia, fatigue, dyspnea, and edema. 3 pts at the first dose level developed asymptomatic Grade 3 hypertriglyceridemia 觸夢顧艱窪醖顧餘網鹽 (壓願餘醖鹹夢膚醖憲艱 )	积极	2020-10-23
ASCO2004	临床1期	HR阳性/HER2低表达实体瘤	15	AGN 195183	蓋艱襯遞製夢餘窪網鏇(蓋衊簾艱選憲餘齋獵繭) = 2 of 4 pts treated had gr 3 elevation of alkaline phosphatase 積鹹製網鬱齋遞廠鏇遞 (積膚餘齋選構製膚憲網 ) 更多	积极	2004-07-15