TC-H 106

TC-H 106 is an inhibitor of Class I Histone Deacetylase with IC50 values of 150, 760, 370 and 5000 nM for HDAC1, HDAC2, HDAC3 and HDAC8, respectively [1].

Histone deacetylases (HADC) are a series of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone and make the histones to wrap the DNA more tightly, which prevent transcription. Class I histone deacetylase are consist of HDAC1, 2, 3 and 8 [1].

In a lymphoblastoid cell line from a Friedreich ataxia patient, TC-H 106 (2 μM) prolonged acetylation of histone H3 [1]. In HeLa cell, TC-H 106 inhibited HDACs with IC50 value of 1.3 μM. TC-H 106 inhibited recombinant HDAC3/NcoR2 and recombinant HDAC1 with IC50 values of 0.79 and 0.24 μM, respectively [2].

In KIKI mice carrying a (GAA) 230 repeats in the first intron of the mouse frataxin gene, TC-H 106 increased the level of frataxin mRNA. The histone H3 and H4 acetylation in chromatin near the GAA repeat was also increased. These results resulted in the frataxin return to the normal level in the nervous system and heart in KIKI mice [3].

References:
[1].  Chou CJ, Herman D, Gottesfeld JM. Pimelic diphenylamide 106 is a slow, tight-binding inhibitor of class I histone deacetylases. J Biol Chem, 2008, 283(51): 35402-35409.
[2].  Xu C, Soragni E, Chou CJ, et al. Chemical probes identify a role for histone deacetylase 3 in Friedreich's ataxia gene silencing. Chem Biol, 2009, 16(9): 980-989.
[3].  Rai M, Soragni E, Jenssen K, et al. HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model. PLoS One, 2008, 3(4): e1958.

Depression and anxiety disorders in chronic hemodialysis patients and their quality of life: A cross-sectional study about 106 cases in the northeast of morocco.[Pubmed:28352018]

Saudi J Kidney Dis Transpl. 2017 Mar-Apr;28(2):341-348.

Hemodialysis (HD) has a severe impact on the life of HD patients. The aim of this work was to assess the prevalence of depression and anxiety disorders, suicidal ideation, and the quality of life among HD patients. Associated factors were also studied. A cross-sectional study was carried out among 103 HD patients treated at the HD Center of Al Farabi Hospital of Oujda during a period of six months in 2015. The Mini-International Neuropsychiatric Interview and European Quality of Life-5 Dimensions (EQ-5D) were used for the assessment. Major depressive episode (MDE) was found in 34% of our patients, whereas anxiety disorder was observed in 25.2%. Suicidal ideation was found in 16.5% and 1.9% of our patients planned their suicide. The EQ-5D index was 0.41 +/- 0.36 and the EQ-Visual Analog Scale score was 45.73 +/- 14. Multivariate analysis showed that MDEs were associated with three factors: marital status, pain, and anxiety disorder. There was also an association between anxiety disorder and age and EQ-Visual Analog Scale score. Suicidal ideation was associated with marital status and anxiety disorders. Together, these results underline the importance of the collaboration between nephrologists and psychiatrists for a better care of HD patients.

Technical Note: Monte Carlo study of (106) Ru/(106) Rh ophthalmic plaques including the (106) Rh gamma spectrum.[Pubmed:28370303]

Med Phys. 2017 Jun;44(6):2581-2585.

PURPOSE: To assess the influence of the (106) Rh gamma spectrum on the Monte Carlo simulation of (106) Ru/(106) Rh ophthalmic plaques, which has been neglected without a quantitative estimation in all previous publications. METHODS: Simulations were run with the penelope 2014 Monte Carlo code for radiation transport. Depth-dose distributions in water were simulated for the plaque models CCA, CCC, CCX and CIA. In addition to the (106) Rh beta spectrum, all gamma components from the (106) Rh gamma spectrum were included in the simulations. Depth-dose curves were compared with those obtained without considering the (106) Rh gamma spectrum. Moreover, half-value (HVL) and tenth-value layers (TVL) were estimated for the (106) Rh gamma spectrum in water, PMMA, stainless steel and lead. Some practical radiation protection applications were discussed. Parallel computing was implemented to reduce computing time. RESULTS: The contribution of the (106) Rh gamma spectrum on the depth-dose curves is negligible at depths of clinical interest. The HVL and TVL of the (106) Rh gamma spectrum were found to be similar to those of (137) Cs. The air-kerma rate at 1 m for a CCA plaque in typical clinical conditions was about 0.4muGym2h-1, resulting in equivalent doses at that point elow 0.05 mSv during a treatment. The air-kerma rate would be underestimated by a factor of 5 if the (106) Rh gamma spectrum were not considered. Also, a freely available software tool was developed to ease parallelization of penelope 2014 simulations that use penmain as steering main program. CONCLUSIONS: The influence of the (106) Rh gamma spectrum is not relevant for clinical purposes, thus validating the common assumption from the literature. However, for simulations at large distances from the plaques, such as for radiation shielding assessment and estimation of dose to personnel, the gamma spectrum from (106) Rh must be taken into account to obtain accurate results.

Transbronchial cryobiopsy in interstitial lung disease: experience in 106 cases - how to do it.[Pubmed:28344982]

ERJ Open Res. 2017 Mar 22;3(1). pii: 00148-2016.

Transbronchial biopsy using forceps (TBB) is the first diagnostic technique performed on patients with interstitial lung disease (ILD). However, the small size of the samples and the presence of artefacts in the tissue obtained make the yield variable. Our objectives were 1) to attempt to reproduce transbronchial cryobiopsy under the same conditions with which we performed conventional TBB, that is, in the bronchoscopy unit without intubating the patient and without fluoroscopy or general anaesthesia; 2) to describe the method used for its execution; and 3) to analyse the diagnostic yield and its complications. We carried out a prospective study that included 106 patients with clinical and radiological features suggestive of ILD who underwent cryo-transbronchial lung biopsy (cryo-TBB) under moderate sedation without endotracheal intubation, general anaesthesia or use of fluoroscopy. We performed the procedure using two flexible bronchoscopes connected to two video processors, which we alternated until obtaining the number of desired samples. A definitive diagnosis was obtained in 91 patients (86%). As for complications, there were five pneumothoraces (4.7%) and in no case was there severe haemorrhage or exacerbation of the underlying interstitial disease. Cryo-TBB following our method is a minimally invasive, rapid, safe and economic technique that can be performed in a bronchoscopy suite under moderate sedation without the need for intubating the patient or using fluoroscopy and without requiring general anaesthesia.

Ruthenium-106 Brachytherapy with or without Additional Local Therapy Shows Favorable Outcome for Variable-Sized Choroidal Melanomas in Korean Patients.[Pubmed:28343376]

Cancer Res Treat. 2018 Jan;50(1):138-147.

PURPOSE: The purpose of this study was to report clinical outcomes of ruthenium-106 ((106)Ru) brachytherapy with or without additional local therapy for choroidal melanomas in Korean patients. MATERIALS AND METHODS: A total of 88 patients diagnosed with choroidal melanomas were treated with (106)Ru brachytherapy between 2006 and 2012. Patients were divided into two groups according to their tumor height: a large group (>/= 6 mm, n=50) and a small group (< 6 mm, n=38). Most patients in the large group received combined therapy with local excision and/or transpupillary thermotherapy. In general, 85-95 Gy was administered to the apex of the tumor, while 100 Gy was administered to the point 2-6 mm from the outer surface of the sclera for patients undergoing combined therapy. RESULTS: The median follow-up duration was 30 months. The 3-year local control rate was significantly higher in the small group than in the large group (94% vs. 70%, p=0.047). The free from distant metastasis (FFDM) rate and the overall survival (OS) rate were also higher in patients in the small group (3-year FFDM, 97% vs. 76%; p=0.031 and 3-year OS, 97% vs. 72%; p=0.036). A total of 13 patients underwent enucleation. The eye-preservation rate was also higher in the small group (3-year eye-preservation rate, 94% vs. 70%; p=0.050), and tumor height was a significant prognostic factor for eye-preservation. CONCLUSION: (106)Ru brachytherapy showed favorable outcomes in small choroidal melanomas in Korean patients. Although additional local treatment could improve eye-preservation rate for large tumors, other strategies should be considered for disease control.

Chemical probes identify a role for histone deacetylase 3 in Friedreich's ataxia gene silencing.[Pubmed:19778726]

Chem Biol. 2009 Sep 25;16(9):980-9.

We recently identified a class of pimelic diphenylamide histone deacetylase (HDAC) inhibitors that show promise as therapeutics in the neurodegenerative diseases Friedreich's ataxia (FRDA) and Huntington's disease. Here, we describe chemical approaches to identify the HDAC enzyme target of these inhibitors. Incubation of a trifunctional activity-based probe with a panel of class I and class II recombinant HDAC enzymes, followed by click chemistry addition of a fluorescent dye and gel electrophoresis, identifies HDAC3 as a unique high-affinity target of the probe. Photoaffinity labeling in a nuclear extract prepared from human lymphoblasts with the trifunctional probe, followed by biotin addition through click chemistry, streptavidin enrichment, and Western blotting also identifies HDAC3 as the preferred cellular target of the inhibitor. Additional inhibitors with different HDAC specificity profiles were synthesized, and results from transcription experiments in FRDA cells point to a unique role for HDAC3 in gene silencing in Friedreich's ataxia.

Pimelic diphenylamide 106 is a slow, tight-binding inhibitor of class I histone deacetylases.[Pubmed:18953021]

J Biol Chem. 2008 Dec 19;283(51):35402-9.

Histone deacetylase (HDAC) inhibitors, including various benzamides and hydroxamates, are currently in clinical development for a broad range of human diseases, including cancer and neurodegenerative diseases. We recently reported the identification of a family of benzamide-type HDAC inhibitors that are relatively non-toxic compared with the hydroxamates. Members of this class of compounds have shown efficacy in cell-based and mouse models for the neurodegenerative diseases Friedreich ataxia and Huntington disease. Considerable differences in IC(50) values for the various HDAC enzymes have been reported for many of the HDAC inhibitors, leading to confusion as to the HDAC isotype specificities of these compounds. Here we show that a benzamide HDAC inhibitor, a pimelic diphenylamide (106), is a class I HDAC inhibitor, demonstrating no activity against class II HDACs. 106 is a slow, tight-binding inhibitor of HDACs 1, 2, and 3, although inhibition for these enzymes occurs through different mechanisms. Inhibitor 106 also has preference toward HDAC3 with K(i) of approximately 14 nm, 15 times lower than the K(i) for HDAC1. In comparison, the hydroxamate suberoylanilide hydroxamic acid does not discriminate between these enzymes and exhibits a fast-on/fast-off inhibitory mechanism. These observations may explain a paradox involving the relative activities of pimelic diphenylamides versus hydroxamates as gene activators.

HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model.[Pubmed:18463734]

PLoS One. 2008 Apr 9;3(4):e1958.

BACKGROUND: Friedreich ataxia, an autosomal recessive neurodegenerative and cardiac disease, is caused by abnormally low levels of frataxin, an essential mitochondrial protein. All Friedreich ataxia patients carry a GAATTC repeat expansion in the first intron of the frataxin gene, either in the homozygous state or in compound heterozygosity with other loss-of-function mutations. The GAA expansion inhibits frataxin expression through a heterochromatin-mediated repression mechanism. Histone modifications that are characteristic of silenced genes in heterochromatic regions occur at expanded alleles in cells from Friedreich ataxia patients, including increased trimethylation of histone H3 at lysine 9 and hypoacetylation of histones H3 and H4. METHODOLOGY/PRINCIPAL FINDINGS: By chromatin immunoprecipitation, we detected the same heterochromatin marks in homozygous mice carrying a (GAA)(230) repeat in the first intron of the mouse frataxin gene (KIKI mice). These animals have decreased frataxin levels and, by microarray analysis, show significant gene expression changes in several tissues. We treated KIKI mice with a novel histone deacetylase inhibitor, compound 106, which substantially increases frataxin mRNA levels in cells from Friedreich ataxia individuals. Treatment increased histone H3 and H4 acetylation in chromatin near the GAA repeat and restored wild-type frataxin levels in the nervous system and heart, as determined by quantitative RT-PCR and semiquantitative western blot analysis. No toxicity was observed. Furthermore, most of the differentially expressed genes in KIKI mice reverted towards wild-type levels. CONCLUSIONS/SIGNIFICANCE: Lack of acute toxicity, normalization of frataxin levels and of the transcription profile changes resulting from frataxin deficiency provide strong support to a possible efficacy of this or related compounds in reverting the pathological process in Friedreich ataxia, a so far incurable neurodegenerative disease.

Pimelic Diphenylamide 106 is a slow, tight-binding inhibitor of class I HDAC (HDAC 1, 2, and 3, with IC50 values of 150 nM , 760nM, and 370 nM, respectively), demonstrating no activity against class II HDACs.

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