Delving into the Latest Updates on Tefinostat with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Tefinostat tartrate

Target

HDACs

Mechanism

HDAC inhibitors(Histone deacetylase inhibitors)

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Philadelphia chromosome positive chronic myelogenous leukemia

Inactive Indication

Chronic Myelomonocytic LeukemiaHepatocellular CarcinomaInflammation+ [1]

Originator Organization

Chroma Therapeutics Ltd.

Active Organization

Chroma Therapeutics Ltd.

Inactive Organization

University of Cardiff

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC28H37N3O5

InChIKeyGLNWREBYRLDPQP-MHZLTWQESA-N

CAS Registry914382-60-8

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.

Start Date01 Jan 2013

Sponsor / Collaborator

Queen Mary University of London

[+1]

NCT00820508 / CompletedPhase 1

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.

Start Date01 Dec 2008

Sponsor / Collaborator

Chroma Therapeutics Ltd.

100 Clinical Results associated with Tefinostat

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100 Translational Medicine associated with Tefinostat

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100 Patents (Medical) associated with Tefinostat

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3

Literatures (Medical) associated with Tefinostat

29 Mar 2016·Oncotarget

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

Article

Author: 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.

01 Jul 2013·British Journal of HaematologyQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: 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

Author: 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 Deals associated with Tefinostat

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15321

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Philadelphia chromosome positive chronic myelogenous leukemia	Phase 2	-	Chroma Therapeutics Ltd.	-
Hepatocellular Carcinoma	Discovery	GB	Chroma Therapeutics Ltd.	01 Jan 2013
Inflammation	Discovery	GB	Chroma Therapeutics Ltd.	29 Jul 2012
Lymphoma	Discovery	NL	Chroma Therapeutics Ltd.	01 Dec 2008
Lymphoma	Discovery	BE	Chroma Therapeutics Ltd.	01 Dec 2008
Lymphoma	Discovery	FR	Chroma Therapeutics Ltd.	01 Dec 2008
Chronic Myelomonocytic Leukemia	Discovery	GB	University of Cardiff	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00820508 (Pubmed \| Int J Radiat Oncol Biol Phys)	Phase 1	Hematologic Neoplasms	18	Tefinostat	lcvvwyosyy(genymrtxtg) = izyuxymwvv gipyzsznte (ygitaongrk )	Positive	01 Jul 2013