1. Cell Cycle/DNA Damage
    Epigenetics
    Autophagy
  2. HDAC
    Autophagy

Entinostat (Synonyms: MS-275; SNDX-275)

Cat. No.: HY-12163 Purity: 98.29%
Data Sheet SDS Handling Instructions

Entinostat is the class I-selective HDAC inhibitor, with IC50 of 243 nM, 453 nM, and 248 nM for HDAC1, HDAC2, and HDAC3.

For research use only. We do not sell to patients.
Entinostat Chemical Structure

Entinostat Chemical Structure

CAS No. : 209783-80-2

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Description

Entinostat is the class I-selective HDAC inhibitor, with IC50 of 243 nM, 453 nM, and 248 nM for HDAC1, HDAC2, and HDAC3.

IC50 & Target

IC50: 243 nM (HDAC1), 453 nM (HDAC2), 248 nM (HDAC3)[1]

In Vitro

Binding affinity of Entinostat (MS-275) against HDAC1 and HDAC2 is 282 nM and 156 nM, respectively[1]. Effects of the HDAC inhibitor Entinostat (MS-275) have been examined in human leukemia and lymphoma cells (U937, HL-60, K562, and Jurkat) as well as in primary acute myelogenous leukemia blasts in relation to differentiation and apoptosis. MS-275 displays dose-dependent effects in each of the cell lines. When administered at a low concentration (e.g., 1 μM), MS-275 exhibits potent antiproliferative activity, inducing p21CIP1/WAF1-mediated growth arrest and expression of differentiation markers (CD11b) in U937 cells. Entinostat (MS-275) potently induces cell death, triggering apoptosis in ~70% of cells at 48 h[2].

In Vivo

Entinostat (MS-27-275) at 49 mg/kg shows marked antitumor effects against KB-3-1, 4-1St, and St-4 tumor lines, and a moderate effect against Capan-1 tumor. Entinostat at 24.5 mg/kg and 12.3 mg/kg also shows significant effects against these tumors. In addition, oral administration of Entinostat apparently increases the level of histone acetylation in HT-29 tumor xenografts 4-24 h after the administration[3]. MS-275 administration (3.5 mg/kg i.p.) to Experimental autoimmune neuritis (EAN) rats once daily from the appearance of first neurological signs greatly reduces the severity and duration of EAN and attenuated local accumulation of macrophages, T cells and B cells, anddemyelination of sciatic nerves. Further, significant reduction of mRNA levels of pro-inflammatory interleukin-1β, interferon-γ, interleukine-17, inducible nitric oxide synthaseand matrix metalloproteinase-9 is observed in sciatic nerves of MS-275 treated EAN rats. In addition, MS-275 treatment increases proportion of infiltrated Foxp3+ cells and anti-inflammatory M2 macrophages in sciatic nerves of EAN rats[4].

Clinical Trial
NCT Number Sponsor Condition Start Date Phase
NCT02897778 Syndax Pharmaceuticals Neoplasms|Neoplasms, Glandular and Epithelial|Neoplasms by Histologic Type|Bronchial Neoplasms|Lung Neoplasms|Respiratory Tract Neoplasms|Thoracic Neoplasms|Digestive System Neoplasms|Endocrine Gland Neoplasms|Carcinoma, Non-Small-Cell Lung|Lung Diseases|Breast Neoplasms|Breast Diseases|Renal Neoplasm|Solid Tumors August 2016 Phase 1
NCT02922946 Syndax Pharmaceuticals Volunteers|Healthy Volunteers|Human Volunteers|Normal Volunteers October 2016 Phase 1
NCT03187015 Syndax Pharmaceuticals Drug Interaction|Healthy Volunteer June 2, 2017 Phase 1
NCT03192111 Syndax Pharmaceuticals Renal Impairment|Healthy Volunteer July 2017 Phase 1
NCT02915523 Syndax Pharmaceuticals|Merck KGaA|Pfizer Epithelial Ovarian Cancer|Peritoneal Cancer|Fallopian Tube Cancer January 10, 2017 Phase 1|Phase 2
NCT03211988 Edward Gelmann|Columbia University Neuroendocrine Tumors August 1, 2017 Phase 2
NCT02833155 EddingPharm Oncology Co., LTD. Breast Cancer July 2016 Phase 1
NCT02922933 Syndax Pharmaceuticals Volunteers|Healthy Volunteers|Human Volunteers|Normal Volunteers November 2016 Phase 1
NCT03179930 Memorial Sloan Kettering Cancer Center|Merck Sharp & Dohme Corp.|Syndax Pharmaceuticals Lymphoma|Relapsed|Refractory June 7, 2017 Phase 2
NCT00866333 Syndax Pharmaceuticals Hodgkin's Lymphoma March 2009 Phase 2
NCT00387465 National Cancer Institute (NCI) Recurrent Non-Small Cell Lung Carcinoma|Stage IIIA Non-Small Cell Lung Cancer|Stage IIIB Non-Small Cell Lung Cancer|Stage IV Non-Small Cell Lung Cancer August 2006 Phase 1|Phase 2
NCT02936752 National Cancer Institute (NCI) Previously Treated Myelodysplastic Syndrome April 3, 2017 Phase 1
NCT02909452 Syndax Pharmaceuticals|Merck Sharp & Dohme Corp. Neoplasms|Neoplasms, Glandular and Epithelial|Neoplasms by Histologic Type|Bronchial Neoplasms|Lung Neoplasms|Respiratory Tract Neoplasms|Thoracic Neoplasms|Digestive System Neoplasms|Endocrine Gland Neoplasms|Carcinoma, Non-Small-Cell Lung|Lung Diseases|Breast Diseases|Renal Neoplasm|Solid Tumors September 2016 Phase 1
NCT00676663 Syndax Pharmaceuticals Breast Cancer|Estrogen Receptor-Positive Breast Cancer|Breast Cancer, Estrogen Receptor-Positive|ER+ Breast Cancer May 2008 Phase 2
NCT02820961 Syndax Pharmaceuticals Breast Cancer|Estrogen Receptor Positive Breast Cancer June 2016 Phase 1
NCT02780804 National Cancer Institute (NCI) Childhood Brain Stem Neoplasm|Childhood Lymphoma|Childhood Solid Neoplasm|Pineal Region Neoplasm|Recurrent Childhood Central Nervous System Neoplasm|Recurrent Childhood Visual Pathway Glioma|Refractory Central Nervous System Neoplasm December 26, 2016 Phase 1
NCT01594398 Syndax Pharmaceuticals Lung Cancer|Non Small Cell Lung Cancer (NSCLC)|Breast Cancer|Estrogen Receptor Breast Cancer May 2012 Phase 1
NCT02708680 Syndax Pharmaceuticals|Roche Pharma AG Breast Cancer May 2016 Phase 1|Phase 2
NCT01132573 National Cancer Institute (NCI) Acute Leukemias of Ambiguous Lineage|Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia|Recurrent Adult Acute Lymphoblastic Leukemia|Untreated Adult Acute Lymphoblastic Leukemia April 2010 Phase 1
NCT01105377 National Cancer Institute (NCI) Recurrent Colon Cancer|Recurrent Rectal Cancer|Stage IV Colon Cancer|Stage IV Rectal Cancer April 2010 Phase 2
NCT02437136 Syndax Pharmaceuticals|Merck Sharp & Dohme Corp. Non-Small Cell Lung Cancer|Melanoma|Mismatch Repair-Proficient Colorectal Cancer July 2015 Phase 1|Phase 2
NCT01434303 National Cancer Institute (NCI) HER2/Neu Positive|Invasive Breast Carcinoma|Recurrent Breast Carcinoma|Stage IV Breast Cancer January 10, 2012 Phase 1
NCT01234532 University of Maryland|Syndax Pharmaceuticals Estrogen Receptor-negative Breast Cancer|HER2-negative Breast Cancer|Progesterone Receptor-negative Breast Cancer|Stage I Breast Cancer|Stage II Breast Cancer|Stage IIIA Breast Cancer|Triple-negative Breast Cancer October 2010 Phase 2
NCT01159301 National Cancer Institute (NCI) Adult Acute Basophilic Leukemia|Adult Acute Eosinophilic Leukemia|Adult Acute Megakaryoblastic Leukemia (M7)|Adult Acute Minimally Differentiated Myeloid Leukemia (M0)|Adult Acute Monoblastic Leukemia (M5a)|Adult Acute Monocytic Leukemia (M5b)|Adult Acute Myeloblastic Leukemia With Maturation (M2)|Adult Acute Myeloblastic Leukemia Without Maturation (M1)|Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities|Adult Acute Myeloid Leukemia With Del(5q)|Adult Acute Myeloid Leukemia With Inv(16) June 2010 Phase 1
NCT03024437 Roberto Pili|Genentech, Inc.|Syndax Pharmaceuticals|Indiana University Metastatic Cancer|Renal Cancer May 25, 2017 Phase 1|Phase 2
NCT00098891 National Cancer Institute (NCI) Adult Grade III Lymphomatoid Granulomatosis|Anaplastic Large Cell Lymphoma|Angioimmunoblastic T-cell Lymphoma|Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue|Intraocular Lymphoma|Nodal Marginal Zone B-cell Lymphoma|Primary Central Nervous System Non-Hodgkin Lymphoma|Recurrent Adult Burkitt Lymphoma|Recurrent Adult Diffuse Large Cell Lymphoma|Recurrent Adult Diffuse Mixed Cell Lymphoma|Recurrent Adult Diffuse Small Cleaved Cell Lymphoma|Recurrent Adult Grade III Lymp October 2004 Phase 1
NCT01383447 National Cancer Institute (NCI) Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia|Recurrent Adult Acute Lymphoblastic Leukemia October 2010 Phase 1|Phase 2
NCT01305499 Case Comprehensive Cancer Center Acute Myeloid Leukemia July 1, 2011 Phase 2
NCT02453620 National Cancer Institute (NCI) Breast Adenocarcinoma|HER2/Neu Negative|Invasive Breast Carcinoma|Metastatic Malignant Solid Neoplasm|Recurrent Breast Carcinoma|Stage III Breast Cancer|Stage IIIA Breast Cancer|Stage IIIB Breast Cancer|Stage IIIC Breast Cancer|Stage IV Breast Cancer|Unresectable Solid Neoplasm November 6, 2015 Phase 1
NCT01349959 National Cancer Institute (NCI) Estrogen Receptor Negative|Estrogen Receptor Positive|HER2/Neu Negative|Male Breast Carcinoma|Progesterone Receptor Negative|Recurrent Breast Carcinoma|Stage IIIC Breast Cancer|Stage IV Breast Cancer|Triple-Negative Breast Carcinoma April 2011 Phase 2
NCT01038778 National Cancer Institute (NCI) Clear Cell Renal Cell Carcinoma|Metastatic Renal Cell Cancer|Stage III Renal Cell Cancer|Stage IV Renal Cell Cancer October 29, 2009 Phase 1|Phase 2
NCT02115594 Syndax Pharmaceuticals Breast Cancer April 2014 Phase 2
NCT01207726 National Cancer Institute (NCI) Stage IA Non-Small Cell Lung Carcinoma|Stage IB Non-Small Cell Lung Carcinoma September 2010 Phase 2
NCT01886573 National Cancer Institute (NCI) Stage IA Non-Small Cell Lung Carcinoma|Stage IB Non-Small Cell Lung Carcinoma|Stage IIA Non-Small Cell Lung Carcinoma|Stage IIB Non-Small Cell Lung Carcinoma|Stage IIIA Non-Small Cell Lung Cancer June 2013 Phase 1
NCT00313586 National Cancer Institute (NCI) Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome|Adult Acute Myeloid Leukemia in Remission|Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11|Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11|Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1|Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL|Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA|Alkylating Agent-Related Acute Myeloid Leukemia|Chronic Myelom August 2006 Phase 2
NCT02697630 Vastra Gotaland Region|Merck Sharp & Dohme Corp.|Syndax Pharmaceuticals Metastatic Uveal Melanoma September 2017 Phase 2
NCT03018249 National Cancer Institute (NCI) Grade 1 Endometrial Endometrioid Adenocarcinoma|Grade 2 Endometrial Endometrioid Adenocarcinoma|Grade 3 Endometrial Endometrioid Adenocarcinoma|Uterine Corpus Adenosarcoma August 25, 2017 Phase 2
NCT00602030 Syndax Pharmaceuticals Non-Small-Cell Lung Carcinoma|Carcinoma, Non-Small Cell Lung December 2007 Phase 1|Phase 2
NCT00101179 National Cancer Institute (NCI) Chronic Myelomonocytic Leukemia|de Novo Myelodysplastic Syndrome|Leukemia|Previously Treated Myelodysplastic Syndrome|Recurrent Adult Acute Myeloid Leukemia|Secondary Acute Myeloid Leukemia|Secondary Myelodysplastic Syndrome|Untreated Adult Acute Myeloid Leukemia November 3, 2004 Phase 1
NCT00828854 Syndax Pharmaceuticals ER+ Breast Cancer April 2008 Phase 2
NCT00462605 National Cancer Institute (NCI) Adult Acute Lymphoblastic Leukemia in Remission|Adult Acute Megakaryoblastic Leukemia (M7)|Adult Acute Minimally Differentiated Myeloid Leukemia (M0)|Adult Acute Monoblastic Leukemia (M5a)|Adult Acute Monocytic Leukemia (M5b)|Adult Acute Myeloblastic Leukemia With Maturation (M2)|Adult Acute Myeloblastic Leukemia Without Maturation (M1)|Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities|Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)|Adult Acute Myeloid Leukemia With t(16;16)(p13;q22 April 2007 Phase 2
NCT02115282 National Cancer Institute (NCI) Estrogen Receptor Positive|HER2/Neu Negative|Male Breast Carcinoma|Progesterone Receptor Positive|Recurrent Breast Carcinoma|Stage IIIB Breast Cancer|Stage IIIC Breast Cancer|Stage IV Breast Cancer March 29, 2014 Phase 3
NCT03215264 Abramson Cancer Center of the University of Pennsylvania Colorectal Cancer July 10, 2017 Phase 1|Phase 2
NCT00020579 National Institutes of Health Clinical Center (CC)|National Cancer Institute (NCI) Cancer March 2001 Phase 1
NCT00015925 Sidney Kimmel Comprehensive Cancer Center|National Cancer Institute (NCI) Leukemia|Multiple Myeloma and Plasma Cell Neoplasm|Myelodysplastic Syndromes|Myelodysplastic/Myeloproliferative Diseases February 2001 Phase 1
NCT01935947 National Cancer Institute (NCI) Recurrent Non-Small Cell Lung Carcinoma|Stage IIIA Non-Small Cell Lung Cancer|Stage IIIB Non-Small Cell Lung Cancer|Stage IV Non-Small Cell Lung Cancer May 2013 Phase 2
NCT01928576 Sidney Kimmel Comprehensive Cancer Center Non-Small Lung Cancer, Epigenetic Therapy August 2013 Phase 2
NCT00466115 Johns Hopkins University Myelodysplastic Syndrome|Acute Myeloid Leukemia April 2007 Phase 2
NCT00185302 Bayer Melanoma December 2004 Phase 2
NCT00754312 Syndax Pharmaceuticals Breast Cancer June 2008 Phase 1
NCT00750698 Syndax Pharmaceuticals Non Small Cell Lung Cancer August 2008 Phase 2
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References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
1 mM 2.6567 mL 13.2834 mL 26.5668 mL
5 mM 0.5313 mL 2.6567 mL 5.3134 mL
10 mM 0.2657 mL 1.3283 mL 2.6567 mL
Kinase Assay
[1]

Biochemical assays of HDAC activity are carried out by Nanosyn in a reaction volume of 10 μL in 384-well microplates. A standard enzymatic reaction contains 5 μL of 2× HDAC inhibitor (e.g., Entinostat), 4 μL of 2.5× enzyme, and 1 μL of 10× substrate in assay buffer (100 mM HEPES, pH 7.5, 25 mM KCl, 0.1% BSA, 0.01% Triton X-100, 1% DMSO). Final concentration of all HDACs in the enzymatic assays is between 0.5 and 5 nM. A final substrate concentration of 1 μM FAM-RHKK(Ac)-NH2 or FAM-RHKK(trifluoroacetyl)-NH2 is used in all assays and found to be below the determined Km,app for each enzyme[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[1]

Entinostat (MS-275) is dissolved in DMSO and stored, and then diluted with appropriate media before use[1].

SH-SY5Y cells are maintained under normal culture conditions in a humidified incubator at 37°C with 5% CO2 and are split twice weekly. Cells are plated in black 384-well plates at 2500 cells/well in 20-μL volume of DMEM/F-12 culture media supplemented with 10% FBS and permitted to adhere overnight. The following day, HDAC inhibitors (e.g., Entinostat) are serially diluted in 100% DMSO, and this series is subsequently cross-diluted into culture media. 5 μL of compound (e.g., Entinostat) diluted in media is added to the appropriate well of the cell plate to afford the indicated final concentration of inhibitor (e.g., Entinostat) with a final 0.1% DMSO. Treated cells are incubated under normal tissue culture conditions for 6, 24, 48, 72, or 96 h prior to quantitation of cellular ATP levels as measured using CellTiter-Glo reagents. Similarly, after 6 h of incubation with HDAC inhibitors (e.g., Entinostat), media from separate cell plates are aspirated, and cells are washed once with media containing no inhibitors. 25 μL of media supplemented with 10% FBS and 0.1% DMSO (no inhibitors) is added back to the cells, and cellular ATP levels are determined using CellTiter-Glo after 24, 48, 72, or 96 h of incubation. Luminescence is measured at each time point using an Envision Instrument with a 0.1 s count time[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[3][4]

Entinostat (MS-27-275) is dissolved in 0.05 N HCl, 0.1% Tween 80 (Mice)[3].
Entinostat (MS-275) is suspended in PBS (Rat)[4].

Mice[3]
A2780 cells (9×106) are suspended in PBS and are injected subcutaneously into the flank of nude mouse. For the other tumor lines, KB-3-1, HCT-15, 4-1St, Calu-3, St-4, Capan-1, and HT-29, tumors are passaged several times before starting in vivo antitumor testing, and a tumor lump (2-3 mm in diameter) is transplanted subcutaneously into the flank of a nude mouse by using a trocar needle. Treatment (four or five mice in each experimental group) with the drugs is started after the tumors are confirmed to have grown in the body (tumor size, 20-100 mm3). Entinostat is administered orally once daily 5 days per week for 4 weeks. Tumor length and width are monitored twice weekly, and tumor volume is calculated.
Rat[4]
Male Lewis rats (8-10 weeks, 170-200 g) are housed under a 12-h light/dark cycle with free access to food and water. For therapeutic treatment, EAN rats receive i.p. injection of MS-275 (3.5 mg/kg) daily from day 10 to day 14 (six rats/group). For injection, MS-275 is suspended in phosphate buffered saline (PBS) and the same volume (1 mL) of PBS is given to control rats. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
M.Wt

376.41

Formula

C₂₁H₂₀N₄O₃

CAS No.

209783-80-2

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

10 mM in DMSO

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

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