Entinostat

Entinostat Property

Melting point:

159-160 ºC

Boiling point:

566.7±50.0 °C(Predicted)

Density 

1.315

storage temp. 

Keep in dark place,Sealed in dry,Store in freezer, under -20°C

solubility 

DMSO: 38 mg/mL, soluble

form 

solid

pka

11.32±0.46(Predicted)

color 

Pale yellow

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 week.

InChI

InChI=1S/C21H20N4O3/c22-18-5-1-2-6-19(18)25-20(26)17-9-7-15(8-10-17)13-24-21(27)28-14-16-4-3-11-23-12-16/h1-12H,13-14,22H2,(H,24,27)(H,25,26)

InChIKey

INVTYAOGFAGBOE-UHFFFAOYSA-N

SMILES

C(OCC1=CC=CN=C1)(=O)NCC1=CC=C(C(NC2=CC=CC=C2N)=O)C=C1

Safety

Hazard Codes 

Xi,T

Risk Statements 

36/37/38-62-48/25-25-61

Safety Statements 

26-36-45

RIDADR 

UN 2811 6.1 / PGIII

WGK Germany 

3

HS Code 

29333990

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Danger

Hazard statements

H301Toxic if swalloed

H360May damage fertility or the unborn child

Precautionary statements

P201Obtain special instructions before use.

Entinostat Chemical Properties,Usage,Production

Description

Entinostat (SNDX-275, MS-275) belongs to benzamide class HDACi and inhibits HDAC1 and 2, 3 and 9 and has low effect against HDAC4, 6, 7 and 8 (Khan et al. 2007). Entinostat is in phase II clinical trial for treatment of Hodgkin's lymphoma and advanced breast cancer (in combination with aromatase inhibitors) and metastatic lung cancer (in combination with erlotinib).

Chemical Properties

Yellow Solid

Uses

Entinostat is an emerging HDACi (histone deacetylase inhibitor). Entinostat is used for treatment of solid tumors and hematologic malignancies. Potent Histone deacetylase inhibitor.

Definition

ChEBI: A member of the class of benzamides resulting from the formal condensation of the carboxy group of the pyridin-3-ylmethyl carbamate derivative of p-(aminomethyl)benzoic acid with one of the amino groups of benzene-1,2-diamine. It is an inhibit r of histone deacetylase isoform 1 (HDAC1) and isoform 3 (HDAC3).

Clinical Use

Entinostat is an HDAC inhibitor with a relatively long half-life (averaging between 33 and 52 hours). Trials have shown significant biological activity in patients with hematological malignancies receiving entinostat treatments. However, the efficacy of entinostat as a single-agent therapy remains limited. Reported dose-limiting toxicities associated with entinostat include neurotoxicity, fatigue, hypophosphatemia, anorexia, and vomiting.
The large number of clinical trials using HDAC inhibitors for the treatment of patients with hematological malignancies has demonstrated that these drugs are relatively well tolerated. Although the responses with the currently-available HDAC inhibitors are still limited, there are significant responses in some patients with advanced disease, where options are limited. With better patient selection and the development of more potent HDAC inhibitors, targeting HDACs for the treatment of hematological malignancies remains promising. Furthermore, a growing body of literature suggests that HDAC inhibitors may potentiate some of the currently used cytotoxic or biologic therapies based on their mechanism of action, with multiple trials currently ongoing. Promising combination partners include proteosome inhibitors, DNA demethylating agents, and anthracyclines.

Synthesis

The general procedure for the synthesis of 4-((2-aminophenyl)carbamoyl)benzylcarbamic acid 3-pyridinylmethyl ester (MS-275) from o-phenylenediamine and 4-((((pyridin-3-ylmethoxy)carbonyl)amino)methyl)benzoic acid was as follows: to a 4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzoic acid (5.0 g, 0.017 mol) THF (100 mL) suspension was added to CDI (3.12 g, 0.019 mol) and the mixture was stirred at 60°C for 3 hours. After acylimidazole formation, the clarified solution was cooled to room temperature. Subsequently, 1,2-phenylenediamine (15.11 g, 0.14 mmol) and trifluoroacetic acid (1.2 mL, 0.015 mol) were added and stirring was continued for 16 hours. After completion of the reaction, THF was removed by evaporation and the crude product was stirred with a mixture of hexane and water (2:5, v/v) for 1 h. The product was filtered and dried. The residue was washed twice by dichloromethane to give pure MS-275 (4) as an off-white powder in 80% yield (5.25 g) with a melting point of 159-160°C. The product was characterized by IR, 1H NMR, and HRMS, and the data were in agreement with those reported in the literature (J Med Chem 1999,42,15,3001-3).

target

HDAC1

storage

+4°C

References

[1] ERDING HU. Identification of novel isoform-selective inhibitors within class I histone deacetylases.[J]. Journal of Pharmacology and Experimental Therapeutics, 2003, 307 2: 720-728. DOI:10.1124/jpet.103.055541
[2] A SAITO. A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors.[J]. Proceedings of the National Academy of Sciences of the United States of America, 1999, 96 8: 4592-4597. DOI:10.1073/pnas.96.8.4592
[3] ILKER Y EYÜPOGLU. Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275.[J]. Molecular Cancer Therapeutics, 2006, 5 5: 1248-1255. DOI:10.1158/1535-7163.mct-05-0533
[4] MS-275, a histone deacetylase inhibitor, selectively induces transforming growth factor beta type II receptor expression in human breast cancer cells
[5] H-S LIN. Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents[J]. British Journal of Pharmacology, 2009, 150 7: 862-872. DOI:10.1038/sj.bjp.0707165
[6] MAMORU FUKUCHI. Class I histone deacetylase-mediated repression of the proximal promoter of the activity-regulated cytoskeleton-associated protein gene regulates its response to brain-derived neurotrophic factor.[J]. The Journal of Biological Chemistry, 2015, 290 11: 6825-6836. DOI:10.1074/jbc.m114.617258