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Entinostat

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Entinostat
Clinical data
Trade namesJingzhuda
Other namesMS-275; MS275; SNDX-275; SNDX275
Routes of
administration		Oral[1]
Drug classHistone deacetylase inhibitor; HDAC1, HDAC2, and HDAC3 inhibitor; Antineoplastic agent
ATC code
Pharmacokinetic data
Elimination half-life33–150 hours[2]
Identifiers
  • (pyridin-3-yl)methyl ({4-[(2-aminophenyl)carbamoyl]phenyl}methyl)carbamate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.158.999 Edit this at Wikidata
Chemical and physical data
FormulaC21H20N4O3
Molar mass376.416 g·mol−1
3D model (JSmol)
  • C1=CC=C(C(=C1)N)NC(=O)C2=CC=C(C=C2)CNC(=O)OCC3=CN=CC=C3
  • 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) X markN
  • Key:INVTYAOGFAGBOE-UHFFFAOYSA-N X markN
 X markNcheckY (what is this?)  (verify)

Entinostat (INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, JANTooltip Japanese Accepted Name), sold under the brand name Jingzhuda and also known by its developmental code names SNDX-275 and MS-275, is a histone deacetylase (HDAC) inhibitor which is used in the treatment of HER2-negative breast cancer.[1][3] It is also under development for the treatment of HER2-positive breast cancer and was previously under development for a large number of other cancers.[1] The drug is taken orally.[1]

Medical uses

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Entinostat is approved for the treatment of HER2-negative breast cancer in China.[1][3]

Side effects

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Side effects of entinostat include fatigue, nausea, vomiting, anorexia, diarrhea, anemia, thrombocytopenia, neutropenia, leukopenia, hypoalbuminemia, hypophosphatemia, hyperglycemia, and hyponatremia, among others.[2]

Pharmacology

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Pharmacodynamics

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Entinostat activities
EnzymeIC50Tooltip Half-maximal inhibitory concentration (nM)
HDAC1243–427
HDAC2306–753
HDAC3248–1,577
HDAC4>100,000
HDAC5>30,000
HDAC6>100,000
HDAC7>30,000
HDAC82,700–82,500
HDAC9>30,000
HDAC1094,700
HDAC11>10,000
Refs: [4][5][6][7][8]

Entinostat is a benzamide histone deacetylase inhibitor.[9][10][11][12] It is a selective inhibitor of the class I HDACs, including HDAC1, HDAC2, and HDAC3, with IC50Tooltip half-maximal inhibitory concentration values of 243 to 453 nM and high selectivity over other HDACs.[4][5][6] However, it has also been reported to inhibit the class IV HDAC11,[2] though findings are mixed.[7]

Pharmacokinetics

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Entinostat shows poor penetration into the brain in non-human primates.[13] The elimination half-life of entinostat is 33 to 150 hours in humans.[2]

History

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Entinostat was first described in the scientific literature, under the developmental code name MS-275, in 1999.[14][15]

Syndax Pharmaceuticals held the rights to entinostat and received $26.6 million in funds to advance treatments of resistant cancers using epigenetic tools in 2016.[16]

Research

[edit]

Entinostat has been studied as a potential reversible male contraceptive.[17]

See also

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References

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  1. 1 2 3 4 5 "EOC Pharma/Syndax Pharmaceuticals". AdisInsight. 21 July 2026. Retrieved 4 August 2026.
  2. 1 2 3 4 Connolly RM, Rudek MA, Piekarz R (June 2017). "Entinostat: a promising treatment option for patients with advanced breast cancer". Future Oncology. 13 (13). London, England: 1137–1148. doi:10.2217/fon-2016-0526. PMC 5618943. PMID 28326839.
  3. 1 2 "Entinostat Tablets Approved for Marketing by China NMPA". National Medical Products Administration. 30 April 2024. Retrieved 4 August 2026.
  4. 1 2 Lauffer BE, Mintzer R, Fong R, Mukund S, Tam C, Zilberleyb I, et al. (September 2013). "Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability". The Journal of Biological Chemistry. 288 (37): 26926–26943. doi:10.1074/jbc.M113.490706. PMC 3772242. PMID 23897821.
  5. 1 2 Abdallah DI, de Araujo ED, Patel NH, Hasan LS, Moriggl R, Krämer OH, et al. (2023). "Medicinal chemistry advances in targeting class I histone deacetylases" (PDF). Exploration of Targeted Anti-Tumor Therapy. 4 (4): 757–779. doi:10.37349/etat.2023.00166. PMC 10497394. PMID 37711592.
  6. 1 2 Tatamiya T, Saito A, Sugawara T, Nakanishi O (1 April 2004). "Isozyme-selective activity of the HDAC inhibitor MS-275". Cancer Research. 64 (7_Supplement). American Association for Cancer Research: 567. ISSN 0008-5472. Retrieved 31 July 2026.
  7. 1 2 Li D, Zhang Z, Li Y, Wang X, Zhong H, Yang H, et al. (May 2023). "Discovery of (S)-N-(2-Amino-4-fluorophenyl)-4-(1-(3-(4-((dimethylamino)methyl)phenyl)-6-oxopyridazin-1(6H)-yl)ethyl)benzamide as Potent Class I Selective HDAC Inhibitor for Oral Anticancer Drug Candidate". Journal of Medicinal Chemistry. 66 (10): 7016–7037. doi:10.1021/acs.jmedchem.3c00525. PMID 37184921. Table 6. Inhibitory Activity (IC50) against HDAC Isoforms 1−11 [...]
  8. ↑ Chen Z, Yang X, Chen Z, Li M, Wang W, Yang R, et al. (October 2023). "A new histone deacetylase inhibitor remodels the tumor microenvironment by deletion of polymorphonuclear myeloid-derived suppressor cells and sensitizes prostate cancer to immunotherapy". BMC Med. 21 (1) 402. doi:10.1186/s12916-023-03094-0. PMC 10601128. PMID 37880708.
  9. ↑ Juergens RA, Vendetti F, Coleman B, Sebree RS, Rudek MA, Belinsky SA, et al. (May 2008). "Phase I trial of 5-azacitidine (5AC) and SNDX-275 in advanced lung cancer (NSCLC)". Journal of Clinical Oncology. 26 (15_suppl): 19036–. doi:10.1200/jco.2008.26.15_suppl.19036.
  10. ↑ Kiany S, Harrison D, Gordon N (2020). "The Histone Deacetylase Inhibitor Entinostat/Syndax 275 in Osteosarcoma". Current Advances in Osteosarcoma. Advances in Experimental Medicine and Biology. Vol. 1257. pp. 75–83. doi:10.1007/978-3-030-43032-0_7. ISBN 978-3-030-43031-3. PMID 32483732. S2CID 219169967.
  11. ↑ Wang Y, Xie Q, Tan H, Liao M, Zhu S, Zheng LL, et al. (November 2021). "Targeting cancer epigenetic pathways with small-molecule compounds: Therapeutic efficacy and combination therapies". Pharmacological Research. 173 105702. doi:10.1016/j.phrs.2021.105702. PMID 34102228. S2CID 235378858.
  12. ↑ Lian B, Chen X, Shen K (2023). "Inhibition of histone deacetylases attenuates tumor progression and improves immunotherapy in breast cancer". Frontiers in Immunology. 14 1164514. Bibcode:2023FrIm...1464514L. doi:10.3389/fimmu.2023.1164514. PMC 10034161. PMID 36969235.
  13. ↑ Hooker JM, Kim SW, Alexoff D, Xu Y, Shea C, Reid A, et al. (2010). "Histone deacetylase inhibitor, MS-275, exhibits poor brain penetration: PK studies of [C]MS-275 using Positron Emission Tomography". ACS Chemical Neuroscience. 1 (1): 65–73. doi:10.1021/cn9000268. PMC 2908422. PMID 20657706.
  14. ↑ Suzuki T, Ando T, Tsuchiya K, Fukazawa N, Saito A, Mariko Y, et al. (July 1999). "Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives". Journal of Medicinal Chemistry. 42 (15): 3001–3003. doi:10.1021/jm980565u. PMID 10425110.
  15. ↑ Saito A, Yamashita T, Mariko Y, Nosaka Y, Tsuchiya K, Ando T, et al. (April 1999). "A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors". Proceedings of the National Academy of Sciences of the United States of America. 96 (8): 4592–4597. Bibcode:1999PNAS...96.4592S. doi:10.1073/pnas.96.8.4592. PMC 16377. PMID 10200307.
  16. ↑ "Company Prepares for Pivotal Phase 3 Study of Entinostat, Most Advanced HDAC Inhibitor in Development for ER+ Metastatic Breast Cancer" (PDF). Syndax Pharmaceuticals. 27 August 2013. Archived from the original (PDF) on 17 June 2016.
  17. ↑ Hong SH, Castro G, Wang D, Nofsinger R, Kane M, Folias A, et al. (February 2024). "Targeting nuclear receptor corepressors for reversible male contraception". Proceedings of the National Academy of Sciences of the United States of America. 121 (9) e2320129121. Bibcode:2024PNAS..12120129H. doi:10.1073/pnas.2320129121. PMC 10907271. PMID 38377195.
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