209783-80-2

Basic information

• Product Name: Entinostat
• Synonyms: Carbamic acid, N-[[4-[[(2-aminophenyl)amino]carbonyl]phenyl]methyl]-, 3-pyridinylmethyl ester;entinostat;3-pyridinylmethyl [[4-[[(2-aminophenyl)amino]carbonyl]phenyl]methyl]carbamate, N-(2-Aminophenyl)-4-[N-(pyridine-3ylmethoxycarbonyl)aminomethyl]benzamide;N-[[4-[[(2-Aminophenyl)amino]carbonyl]phenyl]methyl]carbamic acid 3-pyridinylmethyl ester;Entinostat/MS-275;Nsc706995;Entinostat(NSC-706995);MS-275 (Entinostat)
• CAS NO: 209783-80-2
• Molecular Formula: C₂₁H₂₀N₄O₃
• Molecular Weight: 376.4085
• Product Categories: SNDX 275;Entinostat;Inhibitor;API;Inhibitors
• Mol File: 209783-80-2.mol
• Article Data: 10

Chemical Properties

• Melting Point: 159-160 ºC
• Boiling Point: 566.7 °C at 760 mmHg
• Flash Point: 296.6 °C
• Appearance: /solid
• Density: 1.315
• Vapor Pressure: 7.31E-13mmHg at 25°C
• Refractive Index: 1.672
• Storage Temp.: −20°C
• Solubility: DMSO: 38 mg/mL, soluble
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 week.
• CAS DataBase Reference: Entinostat(CAS DataBase Reference)
• NIST Chemistry Reference: Entinostat(209783-80-2)
• EPA Substance Registry System: Entinostat(209783-80-2)

Safety Data

• Hazard Codes: Xi,T
• Statements: 36/37/38-62-48/25-25-61
• Safety Statements: 26-36-45
• RIDADR: UN 2811 6.1 / PGIII
• WGK Germany: 3
• Hazardous Substances Data: 209783-80-2(Hazardous Substances Data)

Usage

Description

Entinostat, also known as SNDX-275 and MS-275, is a member of the benzamide class of histone deacetylase inhibitors (HDACi). It is a potent inhibitor of histone deacetylase isoforms 1 (HDAC1) and 3 (HDAC3) and has a low effect against HDAC4, 6, 7, and 8. Entinostat is a yellow solid and is currently in phase II clinical trials for the treatment of various types of cancer.

Uses

Used in Anticancer Applications:
Entinostat is used as an emerging HDACi for the treatment of solid tumors and hematologic malignancies. It modulates histone deacetylase activity, which can lead to the reactivation of tumor suppressor genes and the suppression of oncogenes, ultimately inhibiting cancer cell growth and proliferation.
Used in Clinical Trials:
Entinostat is currently being evaluated in phase II clinical trials for the treatment of Hodgkin's lymphoma, advanced breast cancer (in combination with aromatase inhibitors), and metastatic lung cancer (in combination with erlotinib). These trials aim to assess the safety, efficacy, and potential synergistic effects of Entinostat when combined with other cancer treatments.

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.

References

1) Hu et al. (2003), Identification of novel isoform-selective inhibitors within class 1 histone deacetylases; J. Pharmacol. Exp. Ther., 307 720 2) Saito et al. (1999), A synthetic inhibitor of histone deacetylase, MS-275, with marked in vivo antitumor activity against human tumors; Proc. Natl. Acad. Sci. USA, 96 4592 3) Eyupoglu et al. (2006), Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275; Mol. Cancer Ther., 5 1248 4) Lee et al. (2001), MS-275, a histone deacetylase inhibitor, selectively induces transforming growth factor beta type II receptor expression in human breast cancer cells; J. Pharmacol. Exp. Ther., 307 720 5) Lin et al. (2007), Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents; Br. J. Pharmacol., 150 862 6) Fukuchi et al. (2015), 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. Biol. Chem. 290 6825 [Focus Biomolecules Citation]

InChI:InChI=1/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)

Upstream product

• 95-54-5 1,2-diamino-benzene 
• 255894-58-7 1-{4-[N-(pyridin-3-ylmethoxycarbonyl)-aminomethyl]benzoyl}imidazole 
• 100-55-0 3-hydroxymethylpyridin 
• 212632-27-4 pyridin-3-ylmethyl 1H-imidazole-1-carboxylate 
• 241809-79-0 4-benzoic acid 
• 80-73-9 1,3-dimethyl-2-imidazolidinone 
• 1353003-29-8 C₇₂H₆₉N₇O₂₉ 
• 1379471-51-8 C₂₁H₁₈N₆O₃ 
• 209784-84-9 tert-butyl-(2-(4-((2,2,2-trifluoroacetamido)methyl)benzamido)phenyl)carbamate 
• 209784-85-0 [2-(4-aminomethylbenzoylamino)phenyl]carbamic acid tert-butyl ester 
• 530-62-1 1,1'-carbonyldiimidazole 
• 56-91-7 p-aminomethylbenzoic acid 

Downstream Products

• 1037543-21-7 2-[(tert-butoxy)carbonylamino]-N-{2-[(4-{[(3-pyridylmethoxy)-carbonylamino]methyl}phenyl)carbonylamino]phenyl}acetamide 
• 1037543-24-0 4-{[N-(2-{[4-{[3-pyridylmethoxycarbonylamino]methyl}phenyl]carbonylamino}phenyl)carbamoyloxy]methyl}phenyl(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate 
• 1353003-39-0 C₆₆H₆₁N₇O₂₇ 
• 1037543-22-8 2-amino-N-{2-[(4-{[(3-pyridylmethoxy)-carbonylamino]methyl}phenyl)carbonylamino]phenyl}acetamide 
• 1037543-23-9 (N-{[N-(2-{[4-{[3-pyridylmethoxycarbonylamino]methyl}phenyl]carbonylamino}phenyl)-carbamoyl]methyl}carbamoyloxy)methyl(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate 

Relevant articles and documents

Synthesis of n-substituted benzamide derivatives and their evaluation as antitumor agents

Background: Histone deacetylases inhibitors (HDACIs) with different chemical structures have been reported to play an important role in the treatment of cancer. Objective: The study aims to modify the structure of Entinostat (MS-275) to discover new compounds with improved anti-proliferative activities and perform SAR studies on this class of bioactive compounds. Methods: Fourteen N-substituted benzamide derivatives were synthesized and their antiproliferative activities were tested with four cancer cell lines (MCF-7, A549, K562 and MDA-MB231) by MTT assay. Results: Compared with MS-275, six compounds exhibited comparable or even better antiproliferative activities against specific/certain cancer cell lines. Conclusion: The preliminary SARs showed that (i) the 2-substituent of the phenyl ring in the R group and heteroatoms of amide which can chelate with zinc ion are critical to the antiproliferative activity and (ii) chlorine atom or nitro-group on the same benzene ring largely decreases their anti-proliferative activity. Molecular docking study illustrated the interaction (binding affinity) between the synthesized compounds and HDAC2 was observed to be similar to that of MS-275.

CRYSTALLINE FORMS OF ENTINOSTAT

Entinostat is a histone deacetylase inhibitor undergoing clinical investigation in multiple types of solid tumors, such as breast cancer, and hematologic cancers. Crystalline form D and E of Entinostat and crystal form A in high crystal purity are provided. Crystalline form D can be obtained in high chemical purity, exhibits improved water solubility and allows efficient purification of Entinostat with removal of coloured impurities. Processes for the preparation of such crystalline forms and of form A with improved chemical and crystal purity are also provided.

A Heterodimeric Glucuronide Prodrug for Cancer Tritherapy: the Double Role of the Chemical Amplifier

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