Entinostat
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MedKoo CAT#: 201266

CAS#: 209783-80-2

Description: Entinostat, also known as MS-275 or SNDX-275, is a potent HDAC inhibitor with potential antineoplastic activity. Entinostat binds to and inhibits histone deacetylase, an enzyme that regulates chromatin structure and gene transcription. This agent appears to exert dose-dependent effects in human leukemia cells including cyclin-dependent kinase inhibitor 1A (p21/CIP1/WAF1)-dependent growth arrest and differentiation at low drug concentrations; a marked induction of reactive oxygen species (ROS); mitochondrial damage; caspase activation; and, at higher concentrations, apoptosis.


Chemical Structure

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Entinostat
CAS# 209783-80-2

Theoretical Analysis

MedKoo Cat#: 201266
Name: Entinostat
CAS#: 209783-80-2
Chemical Formula: C21H20N4O3
Exact Mass: 376.15354
Molecular Weight: 376.41
Elemental Analysis: C, 67.01; H, 5.36; N, 14.88; O, 12.75

Price and Availability

Size Price Availability Quantity
100.0mg USD 150.0 Ready to ship
200.0mg USD 190.0 Ready to ship
500.0mg USD 350.0 Ready to ship
1.0g USD 650.0 Ready to ship
2.0g USD 950.0 Ready to ship
5.0g USD 2150.0 Ready to ship
10.0g USD 3650.0 Ready to ship
20.0g USD 4950.0 Ready to ship
10.0mM * 1 mL DMSO USD 190.0 Ready to ship
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Synonym: MS275; MS-275; MS 2275; SNDX275; SNDX-275; SNDX 275; Entinostat

IUPAC/Chemical Name: pyridin-3-ylmethyl 4-((2-aminophenyl)carbamoyl)benzylcarbamate.

InChi Key: INVTYAOGFAGBOE-UHFFFAOYSA-N

InChi Code: 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)

SMILES Code: O=C(OCC1=CC=CN=C1)NCC2=CC=C(C(NC3=CC=CC=C3N)=O)C=C2

Appearance: white off white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Entinostat is a class I HDAC inhibitor, with IC50s of 243 nM, 453 nM, and 248 nM for HDAC1, HDAC2, and HDAC3, respectively.
In vitro activity: In summary, entinostat increased surface expression of MICA/B, ULBP1, ULBP2/5/6, HLA, CD155, CD112, and PD-L1 in RD. In A-673, MICA/B surface expression was increased 73% by percent positive (p = 0.21) and 46% by MFI (p = 0.001) (Figure 2A–2D). ULBP1 was increased 216% by percent positive (p = 0.15) and 62% by MFI (p = 0.003). Expression of ULBP2/5/6, ULBP3, HLA, CD155, and CD112 was not significantly changed based on the percent of positive or MFI. However, expression of PD-L1 was increased 151% by percent positive cells (p = 0.06) and 30% by MFI (p = 0.02). In summary, entinostat increased surface expression of MICA/B, ULBP1, and PD-L1 in A-673. Collectively, entinostat significantly upregulated ligands for both activating and inhibitory NK receptors in both RD and A-673. Reference: Oncotarget. 2020 May 19; 11(20): 1799–1815. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244011/
In vivo activity: This study next investigated the antitumor efficacy of ENT and VCR as single agents and in combination in three biologically independent patient-derived tumorgraft xenograft mouse models of pleoRMS. PDX model characteristics are given in Additional file 6: Table S8. In all the cases, ENT had single-agent activity relative to control (Fig. 2e–g). Statistical summaries of three different PDX pleoRMS models are given in Additional file 6: Table S9-S11. Residual end-treatment tumors were examined histologically, and rhabdomyoblastic differentiation was scored for the CTG-800 PDX mouse model, which showed the best response to treatment. There was no difference seen between different treatment groups in terms of rhabdomyoblast differentiation (Additional file 6: Table S12). Representative histology of each treatment group is provided in Additional file 2: Figure S2. Reference: Skelet Muscle. 2019; 9: 12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528217/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 30.0 79.7

Preparing Stock Solutions

The following data is based on the product molecular weight 376.41 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Idso JM, Lao S, Schloemer NJ, Knipstein J, Burns R, Thakar MS, Malarkannan S. Entinostat augments NK cell functions via epigenetic upregulation of IFIT1-STING-STAT4 pathway. Oncotarget. 2020 May 19;11(20):1799-1815. doi: 10.18632/oncotarget.27546. PMID: 32499867; PMCID: PMC7244011. 2. Christmas BJ, Rafie CI, Hopkins AC, Scott BA, Ma HS, Cruz KA, Woolman S, Armstrong TD, Connolly RM, Azad NA, Jaffee EM, Roussos Torres ET. Entinostat Converts Immune-Resistant Breast and Pancreatic Cancers into Checkpoint-Responsive Tumors by Reprogramming Tumor-Infiltrating MDSCs. Cancer Immunol Res. 2018 Dec;6(12):1561-1577. doi: 10.1158/2326-6066.CIR-18-0070. Epub 2018 Oct 19. PMID: 30341213; PMCID: PMC6279584. 3. Bharathy N, Berlow NE, Wang E, Abraham J, Settelmeyer TP, Hooper JE, Svalina MN, Bajwa Z, Goros MW, Hernandez BS, Wolff JE, Pal R, Davies AM, Ashok A, Bushby D, Mancini M, Noakes C, Goodwin NC, Ordentlich P, Keck J, Hawkins DS, Rudzinski ER, Mansoor A, Perkins TJ, Vakoc CR, Michalek JE, Keller C. Preclinical rationale for entinostat in embryonal rhabdomyosarcoma. Skelet Muscle. 2019 May 21;9(1):12. doi: 10.1186/s13395-019-0198-x. PMID: 31113472; PMCID: PMC6528217. 4. Freundt JK, Frommeyer G, Spieker T, Wötzel F, Grotthoff JS, Stypmann J, Hempel G, Schäfers M, Jacobs AH, Eckardt L, Lange PS. Histone deacetylase inhibition by Entinostat for the prevention of electrical and structural remodeling in heart failure. BMC Pharmacol Toxicol. 2019 Mar 6;20(1):16. doi: 10.1186/s40360-019-0294-x. PMID: 30841920; PMCID: PMC6404297.
In vitro protocol: 1. Idso JM, Lao S, Schloemer NJ, Knipstein J, Burns R, Thakar MS, Malarkannan S. Entinostat augments NK cell functions via epigenetic upregulation of IFIT1-STING-STAT4 pathway. Oncotarget. 2020 May 19;11(20):1799-1815. doi: 10.18632/oncotarget.27546. PMID: 32499867; PMCID: PMC7244011. 2. Christmas BJ, Rafie CI, Hopkins AC, Scott BA, Ma HS, Cruz KA, Woolman S, Armstrong TD, Connolly RM, Azad NA, Jaffee EM, Roussos Torres ET. Entinostat Converts Immune-Resistant Breast and Pancreatic Cancers into Checkpoint-Responsive Tumors by Reprogramming Tumor-Infiltrating MDSCs. Cancer Immunol Res. 2018 Dec;6(12):1561-1577. doi: 10.1158/2326-6066.CIR-18-0070. Epub 2018 Oct 19. PMID: 30341213; PMCID: PMC6279584.
In vivo protocol: 1. Bharathy N, Berlow NE, Wang E, Abraham J, Settelmeyer TP, Hooper JE, Svalina MN, Bajwa Z, Goros MW, Hernandez BS, Wolff JE, Pal R, Davies AM, Ashok A, Bushby D, Mancini M, Noakes C, Goodwin NC, Ordentlich P, Keck J, Hawkins DS, Rudzinski ER, Mansoor A, Perkins TJ, Vakoc CR, Michalek JE, Keller C. Preclinical rationale for entinostat in embryonal rhabdomyosarcoma. Skelet Muscle. 2019 May 21;9(1):12. doi: 10.1186/s13395-019-0198-x. PMID: 31113472; PMCID: PMC6528217. 2. Freundt JK, Frommeyer G, Spieker T, Wötzel F, Grotthoff JS, Stypmann J, Hempel G, Schäfers M, Jacobs AH, Eckardt L, Lange PS. Histone deacetylase inhibition by Entinostat for the prevention of electrical and structural remodeling in heart failure. BMC Pharmacol Toxicol. 2019 Mar 6;20(1):16. doi: 10.1186/s40360-019-0294-x. PMID: 30841920; PMCID: PMC6404297.

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1: Schech AJ, Shah P, Yu S, Sabnis GJ, Goloubeva O, Rosenblatt P, Kazi A, Chumsri S, Brodie A. Histone deacetylase inhibitor entinostat in combination with a retinoid downregulates HER2 and reduces the tumor initiating cell population in aromatase inhibitor-resistant breast cancer. Breast Cancer Res Treat. 2015 Jul 2. [Epub ahead of print] PubMed PMID: 26133921.

2: Ruiz R, Raez LE, Rolfo C. Entinostat (SNDX-275) for the treatment of non-small cell lung cancer. Expert Opin Investig Drugs. 2015 Aug;24(8):1101-9. doi: 10.1517/13543784.2015.1056779. Epub 2015 Jun 22. PubMed PMID: 26098363.

3: Schech A, Kazi A, Yu S, Shah P, Sabnis G. Histone Deacetylase Inhibitor Entinostat Inhibits Tumor-Initiating Cells in Triple-Negative Breast Cancer Cells. Mol Cancer Ther. 2015 Jun 2. [Epub ahead of print] PubMed PMID: 26037781.

4: Frys S, Simons Z, Hu Q, Barth MJ, Gu JJ, Mavis C, Skitzki J, Song L, Czuczman MS, Hernandez-Ilizaliturri FJ. Entinostat, a novel histone deacetylase inhibitor is active in B-cell lymphoma and enhances the anti-tumour activity of rituximab and chemotherapy agents. Br J Haematol. 2015 May;169(4):506-19. doi: 10.1111/bjh.13318. Epub 2015 Feb 23. PubMed PMID: 25712263.

5: Vendetti FP, Topper M, Huang P, Dobromilskaya I, Easwaran H, Wrangle J, Baylin SB, Poirier JT, Rudin CM. Evaluation of azacitidine and entinostat as sensitization agents to cytotoxic chemotherapy in preclinical models of non-small cell lung cancer. Oncotarget. 2015 Jan 1;6(1):56-70. PubMed PMID: 25474141; PubMed Central PMCID: PMC4381578.

6: Ngamphaiboon N, Dy GK, Ma WW, Zhao Y, Reungwetwattana T, DePaolo D, Ding Y, Brady W, Fetterly G, Adjei AA. A phase I study of the histone deacetylase (HDAC) inhibitor entinostat, in combination with sorafenib in patients with advanced solid tumors. Invest New Drugs. 2015 Feb;33(1):225-32. doi: 10.1007/s10637-014-0174-6. Epub 2014 Nov 5. PubMed PMID: 25371323.

7: Lee J, Bartholomeusz C, Mansour O, Humphries J, Hortobagyi GN, Ordentlich P, Ueno NT. A class I histone deacetylase inhibitor, entinostat, enhances lapatinib efficacy in HER2-overexpressing breast cancer cells through FOXO3-mediated Bim1 expression. Breast Cancer Res Treat. 2014 Jul;146(2):259-72. doi: 10.1007/s10549-014-3014-7. Epub 2014 Jun 12. PubMed PMID: 24916181; PubMed Central PMCID: PMC4119423.

8: Yang X, Zhang Q, Chen M, Hu L. Pharmacokinetic interaction of entinostat and lapatinib following single and co-oral administration in rats. Xenobiotica. 2014 Nov;44(11):1009-13. doi: 10.3109/00498254.2014.919431. Epub 2014 May 16. PubMed PMID: 24831712.

9: Tellez CS, Grimes MJ, Picchi MA, Liu Y, March TH, Reed MD, Oganesian A, Taverna P, Belinsky SA. SGI-110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome. Int J Cancer. 2014 Nov 1;135(9):2223-31. doi: 10.1002/ijc.28865. Epub 2014 Apr 5. PubMed PMID: 24668305.

10: Prebet T, Sun Z, Figueroa ME, Ketterling R, Melnick A, Greenberg PL, Herman J, Juckett M, Smith MR, Malick L, Paietta E, Czader M, Litzow M, Gabrilove J, Erba HP, Gore SD, Tallman MS. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. J Clin Oncol. 2014 Apr 20;32(12):1242-8. doi: 10.1200/JCO.2013.50.3102. Epub 2014 Mar 24. PubMed PMID: 24663049; PubMed Central PMCID: PMC3986386.

Entinostat

100.0mg / USD 150.0


Additional Information

Entinostat inhibits class I HDAC1 and HDAC3 with IC50 of 0.51 μM and 1.7 μM, respectively.  Entinostat  preferentially inhibits cell proliferation/survival and inactivates downstream signaling in erbB2-overexpressing compared with basal breast cancer cells. Entinostat  reduces the levels of both erbB2 and erbB3, as well as significantly decreases P-erbB2, P-erbB3, P-Akt, and P-MAPK in erbB2-overexpressing cells. Additionally, Entinostat promotes apoptosis and induces cell cycle arrest predominantly at G(1) phase in erbB2-overexpressing cells, whereas Entinostat  mainly induces G(2)-M arrest in basal breast cancer cells. The cellular bias of Entinostat  is shown to be related partly to the levels of erbB3 expression that directly impact the ability of Entinostat  to inhibit proliferation/survival of the erbB2-overexpressing breast cancer cells. These findings show that Entinostat may be developed as a novel therapeutic agent to treat breast cancers with coexpression of both erbB2 and erbB3. see http://www.ncbi.nlm.nih.gov/pubmed/19826038.
 
Entinostat is an orally bioavailable, selective, class I histone deacetylase (HDAC) inhibitor. Entinostat is currently being investigated in randomized, Phase 2 clinical studies in combination with the aromatase inhibitor, exemestane, for the treatment of metastatic or locally advanced ER+ breast cancer; in combination with erlotinib in advanced non-small-cell lung cancer, and in combination with azacitidine in myelodysplastic syndrome. Phase 2 single arm studies in non-small cell lung cancer and colorectal cancer, also are being conducted in combination with azacitidine; and a Phase 2 in Hodgkin's lymphoma is ongoing with single agent entinostat. Entinostat's long half-life allows for weekly or every-other-week oral dosing.