title: The targeted histone deacetylase inhibitor tefinostat (CHR-2845) shows selective in vitro efficacy in monocytoid-lineage leukaemias.
abstract: 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.
authors.affiliation: Department of Haematology, Experimental Cancer Medicine Centre (ECMC), Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Zabkiewicz
authors.affiliation: Department of Haematology, Experimental Cancer Medicine Centre (ECMC), Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Marie
authors.initials: M
authors.lastname: Gilmour
authors.affiliation: Department of Haematology, Experimental Cancer Medicine Centre (ECMC), Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Hills
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Pares
authors.initials: P
authors.lastname: Vyas
authors.affiliation: Chroma Therapeutics, Abingdon, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bone
authors.affiliation: Chroma Therapeutics, Abingdon, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Davidson
authors.affiliation: Department of Haematology, Experimental Cancer Medicine Centre (ECMC), Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Burnett
authors.affiliation: Department of Haematology, Experimental Cancer Medicine Centre (ECMC), Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Knapper
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000098556:mRNA Guanylyltransferases
chemical_list: D000813:Anilides; C586099:CHR 2845; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D003561:Cytarabine; D009713:Nucleotidyltransferases; D000098556:mRNA Guanylyltransferases
keywords: AML; CMML; HDACi; hCE-1; tefinostat