MG 149

MG 149 is an inhibitor of histone acetyltransferases (HAT) with IC50 values of 74μM and 47μM for Tip60 and MOF, respectively [1].

MG 149 is an anacardic acid derivative. It shows selective inhibition towards the MYST type of HATs: Tip60 and MOF with IC50 values of 74μM and 47μM, respectively. The docking study shows that the inhibition of Tip60 by MG 149 is competitive with respect to Ac-CoA in the Ac-CoA binding pocket of Tip60. MG 149 also inhibits the activity of HAT in nuclear extracts from HeLa cells using biotinylated histone H3 or histone H4 peptides as substrates. It is found to be more potent for histone H3 compared to histone H4. Additionally, DNA microarrays demonstrate that MG149 inhibits p53 and NF-kB pathways as well as a very limited number of other pathways [1, 2].

References:
[1] Ghizzoni M, Wu J, Gao T, Haisma HJ, Dekker FJ, George Zheng Y. 6-alkylsalicylates are selective Tip60 inhibitors and target the acetyl-CoA binding site. Eur J Med Chem. 2012 Jan;47(1):337-44.
[2] Dekker FJ, van den Bosch T, Martin NI. Small molecule inhibitors of histone acetyltransferases and deacetylases are potential drugs for inflammatory diseases. Drug Discov Today. 2014 May;19(5):654-60.

Practices of infectious control management during neutropenia: A survey from 149 French hospitals.[Pubmed:28314678]

J Mycol Med. 2017 Jun;27(2):227-231.

OBJECTIVE OF THE STUDY: Neutropenic patients represent a growing and fragile population in our hospitals. Numerous treatments induce neutropenia in haematology wards and elsewhere. Although strict isolation is recommended during post-haematopoietic stem cell transplantation neutropenia, this may not be the current practice in other situations. In this study, our objective was to analyse what protective measures are applied in neutropenic patients in a French survey. MATERIELS AND METHODS: A questionnaire was sent out to infection control teams of 400 public and private French hospitals to enquire about their local recommendations regarding infection prevention in neutropenic patients. RESULTS: Among the 166 (41%) responders, 134 (81%) managed neutropenic patients. All of the centres recommended protective isolation for neutropenic patients. However, only 46 (34%) had clearly defined patients warranting specific isolation measures in terms of the level of neutropenia. All of the centres recommended several barrier measures, but these were highly variable according to the type of air treatment in the wards (note that only 72% of haematology wards are equipped with air treatment). Gowns, gloves, masks, hats and shoe covers were respectively recommended in 128 (95%), 79 (59%), 132 (98%), 87 (65%), and 34 (25%) of the establishments. Surprisingly, the recommendations vary both among hospitals and within the same hospital among different clinical wards. CONCLUSION: In conclusion, protective measures for neutropenic patients are applied variably and urgently require a consensus to homogenize practices.

EphB3-targeted regulation of miR-149 in the migration and invasion of human colonic carcinoma HCT116 and SW620 cells.[Pubmed:28370854]

Cancer Sci. 2017 Mar;108(3):408-418.

microRNAs play key roles during various crucial cell processes such as proliferation, migration, invasion and apoptosis. Also, microRNAs have been shown to possess oncogenic and tumor-suppressive functions in human cancers. Here, we describe the regulation and function of miR-149 in colorectal cancer cell lines. miR-149 expression patterns were detected in human colorectal cell lines and tissue samples, and then focused on its role in regulation of cell growth, migration, invasion, and its target gene identification. Furthermore, the function of the target gene of miR-149 was analyzed in vitro and in vivo. miR-149 expression was downregulated in human colorectal cancer HCT116 and SW620 cell lines compared to the normal colon epithelial NCM460 cell line using quantitative real-time polymerase chain reaction methods. Further studies indicated that introduction of miR-149 was able to suppress cell migration and invasion. Then, EphB3 was identified as a direct target gene of miR-149 in colorectal cancer cells. Moreover, experiments in vitro showed that knockdown expression of EphB3 could suppress cell proliferation and invasion, and ectopic expression of EphB3 restored the phenotypes of CRC cell lines transfected with miR149. In addition, silencing of EphB3 significantly affected cycle progression distribution and increased apoptosis in CRC cell lines. Finally, in vivo results demonstrated that knockdown of EphB3 by siRNA inhibited tumor growth. In conclusion,the important role of miR-149 in colorectal cancer progression suggesting that miR-149 may serve as a therapeutic target for colorectal cancer treatment.

MicroRNA-149 targets specificity protein 1 to suppress human tongue squamous cell carcinoma cell proliferation and motility.[Pubmed:28356969]

Oncol Lett. 2017 Feb;13(2):851-856.

The expression and function of microRNA-149 have been studied in numerous types of cancer. However, thus far, there are no studies of microRNA-149 in tongue squamous cell carcinoma (TSCC). The present study investigated the expression, biological function and molecular mechanism of microRNA-149 in TSCC in vitro, discussing whether it may be a therapeutic biomarker of TSCC in the future. In the present study, microRNA-149 expression in TSCC tissues, matched normal adjacent tissues, TSCC cell lines and normal gingival epithelial cells were analyzed using quantitative polymerase chain reaction. Following transfection with microRNA-149 mimics, cell proliferation, migration and invasion assays, a luciferase assay and western blotting were performed. The present study found that the expression of microRNA-149 was significantly decreased in TSCC tissues and cell lines compared with matched normal tissue and normal gingival epithelial cells, respectively. In addition, it was also demonstrated that microRNA-149 inhibited cell proliferation, migration and invasion by directly targeting specificity protein 1. Therefore, the results suggested that microRNA-149 may be a novel target for TSCC therapy in the future.

Genome-wide profiling of micro-RNA expression in gefitinib-resistant human lung adenocarcinoma using microarray for the identification of miR-149-5p modulation.[Pubmed:28345454]

Tumour Biol. 2017 Mar;39(3):1010428317691659.

To understand the mechanism involved in gefitinib resistance, we established gefitinib-resistant human HCC827/GR-8-1 cell line from the parental HCC827 cell line. We compared the micro-RNA expression profiles of the HCC827 cells HCC827/GR-8-1 using Agilent micro-RNA microarrays. The micro-RNAs, such as the miR-149-5p, were up- or downregulated and associated with acquired gefitinib resistance. Quantitative real-time polymerase chain reaction was then performed to verify the expression patterns of different micro-RNAs. The result showed that miR-149-5p was upregulated in the HCC827/GR-8-1 cell line. To investigate the biological function of miR-149-5p in non-small cell lung cancer cells acquired gefitinib resistance, we examined cell proliferation using a cell counting kit-8 assay. Cell viability was evaluated after the miR-149-5p mimics, inhibitors, and negative control were separately transfected into the non-small cell lung cancer cells. The results showed that the non-small cell lung cancer cells transfected with miR-149-5p mimics exhibited reduced cell motility. The drug-sensitivity assay results revealed that the overexpression of miR-149-5p effectively evaluates the half maximal inhibitory concentration values of the cell in response to gefitinib, and the downregulation of miR-149-5p can attenuate the half maximal inhibitory concentration values of the cell lines in response to gefitinib. Furthermore, the levels of miR-149-5p in the HCC827 and HCC827/GR-8-1 cells were inversely correlated with caspase-3 expression. In conclusion, this study revealed that miR-149-5p is upregulated in the HCC827/GR-8-1 cells and involved in the acquired gefitinib resistance.

MG149 (Tip60 HAT inhibitor) is a selective and potent Tip60 inhibitor with IC50 of 74 uM, similar potentcy for MOF (IC50= 47 uM); little potent for PCAF and p300 (IC50 >200 uM).

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