Tacedinaline - CAS 112522-64-2
Catalog number: 112522-64-2
Category: Inhibitor
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Tacedinaline, also known as CI-944, is an orally bioavailable substituted benzamide derivative with potential antineoplastic activity. Tacedinaline inhibits histone deacetylation, which may result in histone hyperacetylation, followed by the induction of differentiation, the inhibition of cell proliferation, and apoptosis in susceptible tumor cell populations. Check for active clinical trials or closed clinical trials using this agent.
CI994, CI-994, CI 994, PD123654, PD-123654, PD 123654, Tacedinaline, acetyldinaline
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1.Efficacy of acetyldinaline for treatment of minimal residual disease (MRD): preclinical studies in the BNML rat model for human acute myelocytic leukemia.
el-Beltagi HM;Martens AC;Dahab GM;Hagenbeek A Leukemia. 1993 Nov;7(11):1795-800.
The efficacy of acetyldinaline [4-acetylamino-N-(2'-aminophenyl)-benzamide] for eradication of minimal residual disease (MRD), which is left after bone marrow transplantation, and the risk of a bone marrow graft being jeopardized by this treatment was studied in the Brown Norway rat acute myelocytic leukemia model (BNML). To mimic the clinical situation, MRD induction treatment was given to rats showing clinical signs of leukemia and consisted of 80 mg/kg cyclophosphamide and 7.0 Gy X-rays total body irradiation resulting in a 6-8 log leukemic cell kill leaving 10-1000 leukemic cells in the animals. Treatment was completed with a syngeneic bone marrow transplant. A high dose level (HD) treatment of 23.7 mg acetyldinaline/kg per day and a low dose level (LD) treatment of 11.85 mg/kg per day, each given orally for five consecutive days, were compared. The increase in the survival time, the cure rate, and the toxic death rate were evaluated. One 5-day course of LD treatment, started at a time interval of 10, 17, or 24 days following MRD induction, resulted in 44%, 11% or 0% cures. With two 5-day courses of LD treatment, 89%, 22%, or 0% cures were achieved. With LD treatment, maximally an 8 log leukemic cell kill was obtained and no toxicity-related deaths were observed (only less than a 1 log kill of normal hemopoietic stem cells).
2.Cytotoxic chemotherapy regimens that increase dose per cycle (dose intensity) by extending daily dosing from 5 consecutive days to 28 consecutive days and beyond.
Keyes KA;Albella B;LoRusso PM;Bueren JA;Parchment RE Clin Cancer Res. 2000 Jun;6(6):2474-81.
Dose intensity, defined as dose administered per unit time, has emerged as a potentially important measurement of anticancer drug exposure and determinant of efficacy. There are several strategies for increasing dose intensity, one being a protracted daily dosing strategy without major dose reduction for toxicity. This strategy involves continued therapy during periods of recovery from reversible toxicity, and it inherently challenges our understanding that renewing tissues cannot repopulate (recover) in the continued presence of cytotoxic drug. We have tested this idea directly in a murine preclinical trial. Specifically, we have tested whether acutely myelotoxic doses of gemcitabine (i.p. injection, 6.0 mg/m2/day), acetyldinaline [CI-994; GOE 5549; PD 123 654; 4-acetylamino-N-(2'-aminophenyl)-benzamide, 150 mg/m2/day p.o.], and/or melphalan (i.p. injection, 7.2 mg/m2/day) can be tolerated for 28 consecutive days and whether suppressed bone marrow function recovers despite this protracted daily therapy. The three drugs all caused acute neutropenia and suppression of medullary hematopoiesis. Damage to progenitor populations exposed to acetyldinaline and gemcitabine was not as severe as that caused by melphalan, in which case absolute neutrophil count, mature progenitors (colony-forming unit granulocyte/macrophage), and immature progenitors (colony-forming unit-S) progressively declined to severely depressed levels.
3.Morphine-induced synaptic plasticity in the VTA is reversed by HDAC inhibition.
Authement ME;Langlois LD;Kassis H;Gouty S;Dacher M;Shepard RD;Cox BM;Nugent FS J Neurophysiol. 2016 Sep 1;116(3):1093-103. doi: 10.1152/jn.00238.2016. Epub 2016 Jun 15.
Dopamine (DA) dysfunction originating from the ventral tegmental area (VTA) occurs as a result of synaptic abnormalities following consumption of drugs of abuse and underlies behavioral plasticity associated with drug abuse. Drugs of abuse can cause changes in gene expression through epigenetic mechanisms in the brain that underlie some of the lasting neuroplasticity and behavior associated with addiction. Here we investigated the function of histone acetylation and histone deacetylase (HDAC)2 in the VTA in recovery of morphine-induced synaptic modifications following a single in vivo exposure to morphine. Using a combination of immunohistochemistry, Western blot, and whole cell patch-clamp recording in rat midbrain slices, we show that morphine increased HDAC2 activity in VTA DA neurons and reduced histone H3 acetylation at lysine 9 (Ac-H3K9) in the VTA 24 h after the injection. Morphine-induced synaptic changes at glutamatergic synapses involved endocannabinoid signaling to reduce GABAergic synaptic strength onto VTA DA neurons. Both plasticities were recovered by in vitro incubation of midbrain slices with a class I-specific HDAC inhibitor (HDACi), CI-994, through an increase in acetylation of histone H3K9.
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CAS 112522-64-2 Tacedinaline

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