ENTINOSTAT

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H20N4O3
Molecular Weight	376.4085
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC1=CC=CC=C1NC(=O)C2=CC=C(CNC(=O)OCC3=CN=CC=C3)C=C2

InChI

InChIKey=INVTYAOGFAGBOE-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Molecular Formula	C21H20N4O3
Molecular Weight	376.4085
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://adisinsight.springer.com/drugs/800012663
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/17383217 https://www.ncbi.nlm.nih.gov/pubmed/21888556 https://www.ncbi.nlm.nih.gov/pubmed/12975486

Entinostat (MS-275) is an orally active, highly selective, small-molecule histone deacetylase inhibitor (HDACi) derived from benzamide. Entinostat preferentially inhibited HDAC1 versus HDAC3 and had no inhibitory activity toward HDAC8. The time to maximum plasma concentration (tmax) of entinostat ranged from 0.5 to 60h (median of 2h). Elimination of the drug was bi-exponential, with a terminal half-life of 30-80h. Entinostat is a well-tolerated that demonstrates promising therapeutic potential in both solid and hematologic malignancies. Its efficacy does not appear directly dose-related, and as such, more relevant biomarkers are needed to adequately assess its activity.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Histone deacetylase 1 51 Target ID: CHEMBL325 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12975486	Inhibitor 8504		0.3 µM [IC50]
Histone deacetylase 3 35 Target ID: CHEMBL1829 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12975486	Inhibitor 8504		8.0 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Breast cancer 432 Sources: http://adisinsight.springer.com/drugs/800012663	Primary	Phase III 665	Unknown Approved Use Unknown
Non-small cell lung cancer 211 Sources: http://adisinsight.springer.com/drugs/800012663	Primary	Phase II 1147	Unknown Approved Use Unknown
Acute myeloid leukemia 141 Sources: http://adisinsight.springer.com/drugs/800012663	Primary	Phase II 1147	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
45.1 ng/mL REVIEW https://pubmed.ncbi.nlm.nih.gov/28326839/	10 mg/kg 1 times / 2 weeks multiple, oral dose: 10 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered:		ENTINOSTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
114.3 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/22134508	4 mg/m² 1 times / week multiple, oral dose: 4 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: Isotretinoin	Isotretinoin	ENTINOSTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
529 ng × h/mL REVIEW https://pubmed.ncbi.nlm.nih.gov/28326839/	10 mg/kg 1 times / 2 weeks multiple, oral dose: 10 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered:		ENTINOSTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
586.6 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/22134508	4 mg/m² 1 times / week multiple, oral dose: 4 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: Isotretinoin	Isotretinoin	ENTINOSTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
51.6 h REVIEW https://pubmed.ncbi.nlm.nih.gov/28326839/	10 mg/kg 1 times / 2 weeks multiple, oral dose: 10 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered:		ENTINOSTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
129.7 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/22134508	4 mg/m² 1 times / week multiple, oral dose: 4 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: Isotretinoin	Isotretinoin	ENTINOSTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
18.8% EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16028097/	10 mg/m² single, oral dose: 10 mg/m² route of administration: Oral experiment type: SINGLE co-administered:		ENTINOSTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2252			inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYPs 29 P-gp 1741	OATP1B3 435 UGTs 13 OATP1B1 503 CYPs 33	BCRP 101 CYP19 1

Drug as perpetrator

Target	Modality	Activity
BCRP 985	inducer 1966 Sources: https://pubmed.ncbi.nlm.nih.gov/26133921/	no
CYP3A4 2633	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/609494#sid=103197084	yes [IC50 0.73 uM]
P-gp 1932	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363676644 \| https://pubmed.ncbi.nlm.nih.gov/29979729/	yes [IC50 9.2 uM]
CYP19 2	inducer 1966 Sources: https://pubmed.ncbi.nlm.nih.gov/21245100/	yes
CYPs 35	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/28326839/	yes

Drug as victim

Target	Modality	Activity
CYPs 33	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/16583304/	no
OATP1B1 503	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/16583304/	no
OATP1B3 435	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/16583304/	no
UGTs 13	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/16583304/	no

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://pubmed.ncbi.nlm.nih.gov/21742496/ \| https://pubmed.ncbi.nlm.nih.gov/21650221/

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P002KUN	https://www.1pchem.com/search?query=1P002KUN
A2B Chem	AB19535	http://a2bchem.com/prod/AB19535
AChemBlock	M15388	http://www.achemblock.com/catalogsearch/result/?q=M15388
Achemo Scientific Limited	AC-66533	http://www.achemo.com/search/?Keyword=AC-66533
AK Scientific	V2451	https://aksci.com/item_detail.php?cat=V2451
Ambeed	A122285	http://www.ambeed.com/search/Search.html?keyword=A122285
AOBIOUS INC	AOB2570	http://aobious.com/aobious/search?search_query=AOB2570
ApexBio Technology	A8171	https://www.apexbt.com/catalogsearch/result/?q=A8171
AstaTech	41168	http://astatechinc.com/CPSResult.php?CRNO=41168
Axon MedChem	1803	https://www.axonmedchem.com/product/1803
BioSynth	W-201831	https://www.biosynth.com/en/products/life-science/other-biochemicals/products/W-201831
BOC Sciences	209783-80-2	http://www.bocsci.com/description.asp?cas=209783-80-2
Capot Chemical	24433	https://www.capotchem.com/search.do?q=24433
Cayman Chemical	13284	http://www.caymanchem.com/app/template/Product.vm/catalog/13284
Chem Scene	CS-0511	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0511
ChemShuttle	140489	https://www.chemshuttle.com/catalogsearch/result/?q=140489
ChemShuttle	149125	https://www.chemshuttle.com/catalogsearch/result/?q=149125
eMolecules	222573108	https://orderbb.emolecules.com/search/#?query=222573108
eMolecules	252359243	https://orderbb.emolecules.com/search/#?query=252359243
eMolecules	31239709	https://orderbb.emolecules.com/search/#?query=31239709
Enamine	EN300-6488260	https://www.enaminestore.com/catalog/EN300-6488260
eNovation Chemicals	D395222	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D395222&searchbtn.x=0&searchbtn.y=0
eNovation Chemicals	D586663	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D586663&searchbtn.x=0&searchbtn.y=0
Excenen	EX-A038	http://www.excenen.com/searchresultlist.php?id=EX-A038
Exclusive Chemistry	2117	http://www.exchemistry.com/chem-catalog/product-2117.html
Fluorochem	50699	http://www.fluorochem.co.uk/Products/Product?code=050699
Hairui	ENJL011	http://www.hairuichem.com/en/product/search.do?q=ENJL011
KeyOrganics	AS-17906	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-17906
Lab Network	LN01285798	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01285798
mcule	MCULE-6200347297	https://mcule.com/MCULE-6200347297/
mcule	MCULE-9534048478	https://mcule.com/MCULE-9534048478/
MedChem Express	HY-12163	https://www.medchemexpress.com/search.html?q=HY-12163&ft=&fa=&fp=
Molnova	M13310	https://www.molnova.com/en/serch-list.html?keywords=M13310
MolPort	MolPort-005-942-713	https://www.molport.com/shop/molecule-link/MolPort-005-942-713
MuseChem	I002611	https://www.musechem.com/product/I002611.html
PI Chemicals	PI-38652	http://www.pipharm.com/catalog_products/PI-38652.html
Selleck Chemicals	S1053	http://www.selleckchem.com/search.html?searchDTO.searchParam=S1053
ShangHai Biochempartner	BCP000127	http://www.biochempartner.com/search_BCP000127
ShangHai Biochempartner	BCP01824	http://www.biochempartner.com/search_BCP01824
TargetMol	T6233	https://www.targetmol.com/search?keyword=T6233
Toronto Research Chemicals	E559300	https://www.trc-canada.com/product-detail/?CatNum=E559300
W&J PharmaChem	RT-	http://wjpharmachem.com/new/searcht.php?keyword=RT-

PubMed

Title	Date	PubMed
MS275 enhances cytotoxicity induced by 5-fluorouracil in the colorectal cancer cells.	2010-02-10	19853597
Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation.	2010-01-07	19802013
HDAC inhibitor SNDX-275 induces apoptosis in erbB2-overexpressing breast cancer cells via down-regulation of erbB3 expression.	2009-11-01	19826038
Three epigenetic drugs up-regulate homeobox gene Rhox5 in cancer cells through overlapping and distinct molecular mechanisms.	2009-11	19679824
MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation.	2009-10-15	19652201
Efficacy of MS-275, a selective inhibitor of class I histone deacetylases, in human colon cancer models.	2009-10	19724929
Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies.	2009-09-24	19546476
HDAC inhibitors, MS275 and SBHA, enhances cytotoxicity induced by oxaliplatin in the colorectal cancer cell lines.	2009-09-18	19596269
Anti-leukemia activity of MS-275 histone deacetylase inhibitor implicates 4-1BBL/4-1BB immunomodulatory functions.	2009-09-17	19759901
Antidepressant actions of histone deacetylase inhibitors.	2009-09-16	19759294
Histone deacetylase inhibitors cooperate with IFN-gamma to restore caspase-8 expression and overcome TRAIL resistance in cancers with silencing of caspase-8.	2009-09-03	19597472
Epigenetic influences on sensory regeneration: histone deacetylases regulate supporting cell proliferation in the avian utricle.	2009-09	19340485
Lysine acetylation targets protein complexes and co-regulates major cellular functions.	2009-08-14	19608861
DNER, an epigenetically modulated gene, regulates glioblastoma-derived neurosphere cell differentiation and tumor propagation.	2009-07	19544453
Reactivation of death receptor 4 (DR4) expression sensitizes medulloblastoma cell lines to TRAIL.	2009-07	19148581
Clinical studies of histone deacetylase inhibitors.	2009-06-15	19509172
Epigenetic modifiers: basic understanding and clinical development.	2009-06-15	19509169
"Shock and kill" effects of class I-selective histone deacetylase inhibitors in combination with the glutathione synthesis inhibitor buthionine sulfoximine in cell line models for HIV-1 quiescence.	2009-06-02	19486542
[MS-275, a histone deacetylase inhibitor, induces apoptosis and alters survivin gene expression in human myeloma cell line U266].	2009-05	19624872
Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic cells: potential for therapy of myeloid leukemia and myelodysplastic syndromes.	2009-05	19407318
Epigenetic modulation of mGlu2 receptors by histone deacetylase inhibitors in the treatment of inflammatory pain.	2009-05	19255242
Histone deacetylase inhibitors promote apoptosis and senescence in human mesenchymal stem cells.	2009-05	18694296
[Effects of histone deacetylase inhibitor MS-275 on expression of survivin and NF-kappaB in the human myeloma cell line U266 cells].	2009-04	19615275
Rescue of major histocompatibility-DR surface expression in retinoblastoma-defective, non-small cell lung carcinoma cells by the MS-275 histone deacetylase inhibitor.	2009-03	19252299
The reelin and GAD67 promoters are activated by epigenetic drugs that facilitate the disruption of local repressor complexes.	2009-02	19029285
Histone acetylation resulting in resistance to methotrexate in choroid plexus cells.	2009-02	18853233
Determination of a benzamide histone deacetylase inhibitor, MS-275, in human plasma by liquid chromatography with mass-spectrometric detection.	2009-01-15	19117815
Induction of Foxp3+ regulatory T cells with histone deacetylase inhibitors.	2009	19358983
Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer.	2008-12-15	18798265
Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells.	2008-12	18784743
The histone-deacetylase inhibitor MS-275 and the CDK-inhibitor CYC-202 promote anti-tumor effects in hepatoma cell lines.	2008-11	18949429
Experimental study on inhibitory effects of histone deacetylase inhibitor MS-275 and TSA on bladder cancer cells.	2008-09-04	19181544
MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells.	2008-09	18394702
Sp1-mediated TRAIL induction in chemosensitization.	2008-08-15	18701496
Pharmacodynamic assessment of histone deacetylase inhibitors: infrared vibrational spectroscopic imaging of protein acetylation.	2008-08-15	18651756
Multicenter phase II trial of the histone deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate in pretreated metastatic melanoma.	2008-08	18626312
A phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas.	2008-07-15	18579665
Inhibition of MEK/ERK signaling synergistically potentiates histone deacetylase inhibitor-induced growth arrest, apoptosis and acetylation of histone H3 on p21waf1 promoter in acute myelogenous leukemia cell.	2008-07	18185526
p21(WAF1/CIP1) induction by 5-azacytosine nucleosides requires DNA damage.	2008-06-05	18223691
Histone deacetylase inhibitors induce growth arrest, apoptosis, and differentiation in clear cell sarcoma models.	2008-06	18566246
Evaluation of the in vitro and in vivo antitumor activity of histone deacetylase inhibitors for the therapy of retinoblastoma.	2008-05-15	18483379
Potentiation of reactive oxygen species is a marker for synergistic cytotoxicity of MS-275 and 5-azacytidine in leukemic cells.	2008-05	18031811
MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours.	2008-04-08	18349838
Identification of ligand features essential for HDACs inhibitors by pharmacophore modeling.	2008-04	18061500
Probing the elusive catalytic activity of vertebrate class IIa histone deacetylases.	2008-03-15	18308563
Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts.	2008-03-15	18166465
Histone deacetylase inhibitors in lymphoma and solid malignancies.	2008-03	18366289
Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors.	2008-01-15	17868033
Antiproliferative activities of a library of hybrids between indanones and HDAC inhibitor SAHA and MS-275 analogues.	2007-11-15	17897824
Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid malignancies.	2007-09-15	17875771

Patents

Sample Use Guides

In Vivo Use Guide

Phase I trial data have shown that daily dosing of entinostat is not tolerated. Administration of the drug every 2 weeks or weekly at doses of ≤10 mg/m2 was much better tolerated than daily dosing. The recommended phase II dose for entinostat is 4 mg/ m2 once weekly (solid tumors).

Route of Administration: Oral

In Vitro Use Guide

Entinostat (MS-275) exerts dose-dependent effects in human leukemia cells, i.e., p21(CIP1/WAF1)-dependent growth arrest and differentiation at low drug concentrations (e.g., 1 uM) and a marked induction of ROS, mitochondrial damage, caspase activation, and apoptosis at higher concentrations (e.g., 5 uM).

Substance Class	Chemical Created by `admin` on `Mon Mar 31 18:15:14 GMT 2025` Edited by `admin` on `Mon Mar 31 18:15:14 GMT 2025`
Record UNII	1ZNY4FKK9H
Record Status	`Validated (UNII)`
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Name

Type

Language

ENTINOSTAT

Official Name

English

MS-27-275

Preferred Name

English

Entinostat [WHO-DD]

Common Name

English

ENTINOSTAT [USAN]

Common Name

English

Pyridin-3-ylmethyl ({4-[(2-aminophenyl)carbamoyl]phenyl}methyl)carbamate

Systematic Name

English

CARBAMIC ACID, N-((4-(((2-AMINOPHENYL)AMINO)CARBONYL)PHENYL)METHYL)-, 3- PYRIDINYLMETHYL ESTER

Common Name

English

entinostat [INN]

Common Name

English

MS-275-27

Code

English

ENTINOSTAT [JAN]

Common Name

English

SNDX-275

Code

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/10/732