Tefinostat(Tefinostat) - 药物靶点：HDACs_在研适应症：费城染色体阳性慢性粒细胞白血病_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Tefinostat tartrate

靶点

HDACs

作用机制

HDAC抑制剂(组蛋白去乙酰化酶家族抑制剂)

治疗领域

肿瘤血液及淋巴系统疾病

在研适应症

费城染色体阳性慢性粒细胞白血病

非在研适应症

慢性粒单核细胞白血病肝细胞癌炎症+ [1]

原研机构

Chroma Therapeutics Ltd.

在研机构

Chroma Therapeutics Ltd.

非在研机构

University of Cardiff

最高研发阶段临床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C28H37N3O5

InChIKeyGLNWREBYRLDPQP-MHZLTWQESA-N

CAS号914382-60-8

关联

3

项与 Tefinostat 相关的临床试验

EUCTR2015-002281-23-GB / Not yet recruiting临床2期

A phase 2 study of the monocyte-targeted histone deacetylase inhibitor tefinostat (CHR-2845) in chronic myelomonocytic leukaemia (CMML) - Monocle

开始日期2016-06-13

申办/合作机构

University of Cardiff

NCT02759601 / Unknown status临床1/2期

A Phase I/II Dose Escalation Trial of HDAC Inhibitor Tefinostat for Cancer Associated Inflamation in Hepatocellular Carcinoma

This study is being carried out to assess the best dose of a new drug, called tefinostat, in treating liver cancer.
Tefinostat is a new drug that blocks enzymes called histone deacetylases (pronounced dee-as-et-isle-azes). Cells need these enzymes to grow and divide. Blocking them may stop cancer growing. Drugs that block these enzymes are called histone deacetylase inhibitors or 'HDAC inhibitors'.
Tefinostat has never been given to patients with liver cancer before so it isn't known which dose is best at treating liver cancer. To find this out the study will be testing one dose and if that is safe, then test a higher dose and so on.
The aim of this study is to find the best dose of tefinostat without causing side effects. The study will be looking closely at any side effects patients might experience from this treatment.

开始日期2013-01-01

申办/合作机构

Queen Mary University of London

[+1]

NCT00820508 / Completed临床1期

A Phase I Study to Evaluate the Safety and Tolerability of the Histone Deacetylase Inhibitor, CHR-2845, in Patients With Advanced or Treatment Refractory Haematological Diseases or Lymphoid Malignancies

The purpose of this study is to determine whether the histone deacetylase inhibitor CHR-2845 is tolerated in patients with haematological diseases and lymphoid malignancies.

开始日期2008-12-01

申办/合作机构

Chroma Therapeutics Ltd.

100 项与 Tefinostat 相关的临床结果

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100 项与 Tefinostat 相关的转化医学

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100 项与 Tefinostat 相关的专利（医药）

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3

项与 Tefinostat 相关的文献（医药）

2016-03-29·Oncotarget

The targeted histone deacetylase inhibitor tefinostat (CHR-2845) shows selective in vitro efficacy in monocytoid-lineage leukaemias

Article

作者: Vyas, Pares ; Davidson, Alan ; Burnett, Alan ; Zabkiewicz, Joanna ; Knapper, Steven ; Hills, Robert ; Gilmour, Marie ; Bone, Elizabeth

Tefinostat (CHR-2845) is a novel monocyte/macrophage-targeted histone deacetylase (HDAC) inhibitor which is cleaved into its active acid by the intracellular esterase human carboxylesterase-1 (hCE-1). The in vitro efficacy of tefinostat was characterised in cell lines and in a cohort of 73 primary AML and CMML samples. Dose-dependent induction of apoptosis and significant growth inhibitory effects were seen in myelomonocytic (M4), monocytic/monoblastic (M5) and CMML samples in comparison to non-monocytoid AML sub-types (p = 0.007). Importantly, no growth inhibitory effects were seen in normal bone marrow CD34+ cells exposed to AML-toxic doses of tefinostat in clonogenic assays. Expression of hCE-1 was measured by intracellular flow cytometry and immunoblotting across the cohort, with highest levels seen in M5 AML patients. hCE-1 levels correlated with significantly increased tefinostat sensitivity (low EC50) as measured by growth inhibition assays (p = 0.001) and concomitant elevation of the mature monocytoid marker CD14+. Strong induction of intracellular histone protein acetylation was observed in tefinostat-responsive samples, as were high levels of the DNA damage sensor γ-H2A.X, highlighting potential biomarkers of patient responsiveness. Synergistic interaction between tefinostat and the current standard treatment cytarabine was demonstrated in dose response and clonogenic assays using simultaneous drug addition in primary samples (median Combination Index value = 0.51). These data provide a strong rationale for the further clinical evaluation of tefinostat in monocytoid-lineage haematological neoplasms including CMML and monocyte-lineage AMLs.

2013-07-01·British Journal of Haematology2区 · 医学

A phase I first‐in‐human study with tefinostat – a monocyte/macrophage targeted histone deacetylase inhibitor – in patients with advanced haematological malignancies

2区 · 医学

Article

作者: Van de Loosdrecht, Arjan A. ; Davidson, Alan H. ; Zachee, Pierre ; Wells, Graham ; Hooftman, Leon ; Breems, Dimitri ; Ossenkoppele, Gert J. ; Lowenberg, Bob ; Vey, Norbert ; Needham, Lindsey ; Toal, Martin ; Debnam, Phillip M. ; Bawden, Lindsay

SummaryTefinostat (CHR‐2845) is a monocyte/macrophage targeted histone deacetylase inhibitor (HDACi). This first‐in‐human, standard 3 + 3 dose escalating trial of oral, once daily tefinostat was conducted to determine the safety, tolerability, pharmacokinetic and pharmacodynamic profile of tefinostat in relapsed/refractory haematological diseases. Eighteen patients were enrolled at doses of 20–640 mg. Plasma concentrations of tefinostat exceeded those demonstrated to give in vitro anti‐proliferative activity. Flow cytometric pharmacodynamic assays demonstrated monocyte‐targeted increases in protein acetylation, without corresponding changes in lymphocytes. Dose‐limiting toxicities (DLTs) were not observed and dose escalation was halted at 640 mg without identification of the maximum tolerated dose. Drug‐related toxicities were largely Common Toxicity Criteria for Adverse Events grade 1/2 and included nausea, anorexia, fatigue, constipation, rash and increased blood creatinine. A patient with chronic monomyelocytic leukaemia achieved a bone marrow response, with no change in peripheral monocytes. An acute myeloid leukaemia type M2 patient showed a >50% decrease in bone marrow blasts and clearance of peripheral blasts. In conclusion, tefinostat produces monocyte‐targeted HDACi activity and is well tolerated, without the DLTs, e.g. fatigue, diarrhoea, thrombocytopenia, commonly seen with non‐targeted HDACi. The early signs of efficacy and absence of significant toxicity warrant further evaluation of tefinostat in larger studies. (clinicaltrials.gov identifier: NCT00820508).

Biomolecules

Efficacy of HDAC Inhibitors in Driving Peroxisomal β-Oxidation and Immune Responses in Human Macrophages: Implications for Neuroinflammatory Disorders

Article

作者: Forss-Petter, Sonja ; Villoria-González, Andrea ; Parzer, Patricia ; Zierfuss, Bettina ; Rommer, Paulus ; Zujovic, Violetta ; Waidhofer-Söllner, Petra ; Weinhofer, Isabelle ; Berger, Johannes ; Göpfert, Jens ; Heuböck, Elisabeth ; Ponleitner, Markus

Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary peroxisomal alterations is featured in neurodegenerative and neuroinflammatory disorders such as X-linked adrenoleukodystrophy and multiple sclerosis (MS). Here, we identified that healthy human macrophages upregulate the peroxisomal genes involved in β-oxidation during myelin phagocytosis and pro-inflammatory activation, and that this response is impaired in peripheral macrophages and phagocytes in brain white matter lesions in MS patients. The pharmacological targeting of VLCFA metabolism and peroxisomes in innate immune cells could be favorable in the context of neuroinflammation and neurodegeneration. We previously identified the epigenetic histone deacetylase (HDAC) inhibitors entinostat and vorinostat to enhance VLCFA degradation and pro-regenerative macrophage polarization. However, adverse side effects currently limit their use in chronic neuroinflammation. Here, we focused on tefinostat, a monocyte/macrophage-selective HDAC inhibitor that has shown reduced toxicity in clinical trials. By using a gene expression analysis, peroxisomal β-oxidation assay, and live imaging of primary human macrophages, we assessed the efficacy of tefinostat in modulating VLCFA metabolism, phagocytosis, chemotaxis, and immune function. Our results revealed the significant stimulation of VLCFA degradation with the upregulation of genes involved in peroxisomal β-oxidation and interference with immune cell recruitment; however, tefinostat was less potent than the class I HDAC-selective inhibitor entinostat in promoting a regenerative macrophage phenotype. Further research is needed to fully explore the potential of class I HDAC inhibition and downstream targets in the context of neuroinflammation.

100 项与 Tefinostat 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15321

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
费城染色体阳性慢性粒细胞白血病	临床2期	-	Chroma Therapeutics Ltd.	-
肝细胞癌	药物发现	英国	Chroma Therapeutics Ltd.	2013-01-01
炎症	药物发现	英国	Chroma Therapeutics Ltd.	2012-07-29
淋巴瘤	药物发现	荷兰	Chroma Therapeutics Ltd.	2008-12-01
淋巴瘤	药物发现	比利时	Chroma Therapeutics Ltd.	2008-12-01
淋巴瘤	药物发现	法国	Chroma Therapeutics Ltd.	2008-12-01
慢性粒单核细胞白血病	药物发现	英国	University of Cardiff	-

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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


NCT00820508 (Pubmed \| Int J Radiat Oncol Biol Phys)	临床1期	血液肿瘤	18	Tefinostat	簾廠範蓋夢膚鹽鑰遞窪(獵築醖範憲蓋窪鹽繭鏇) = 蓋繭壓簾淵觸襯艱壓網積築選鬱簾餘齋餘製餘 (選築夢願築築選鏇鬱選 )	积极	2013-07-01