Chemistry:Entinostat
Entinostat (INN, USAN, JAN), 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][2] 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
Entinostat is approved for the treatment of HER2-negative breast cancer in China.[1][2]
Side effects
Side effects of entinostat include fatigue, nausea, vomiting, anorexia, diarrhea, anemia, thrombocytopenia, neutropenia, leukopenia, hypoalbuminemia, hypophosphatemia, hyperglycemia, and hyponatremia, among others.[3]
Pharmacology
Pharmacodynamics
| Enzyme | IC50 (nM) |
|---|---|
| HDAC1 | 243–427 |
| HDAC2 | 306–753 |
| HDAC3 | 248–1,577 |
| HDAC4 | >100,000 |
| HDAC5 | >30,000 |
| HDAC6 | >100,000 |
| HDAC7 | >30,000 |
| HDAC8 | 2,700–82,500 |
| HDAC9 | >30,000 |
| HDAC10 | 94,700 |
| 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 IC50 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,[3] though findings are mixed.[7]
Pharmacokinetics
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.[3]
History
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
Entinostat has been studied as a potential reversible male contraceptive.[17]
See also
References
- ↑ 1.0 1.1 1.2 1.3 "EOC Pharma/Syndax Pharmaceuticals". 21 July 2026. https://adisinsight.springer.com/drugs/800012663.
- ↑ 2.0 2.1 "Entinostat Tablets Approved for Marketing by China NMPA". 30 April 2024. https://english.nmpa.gov.cn/2024-04/30/c_1049692.htm.
- ↑ 3.0 3.1 3.2 Cite error: Invalid
<ref>tag; no text was provided for refs namedConnollyRudekPiekarz2017 - ↑ 4.0 4.1 "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. September 2013. doi:10.1074/jbc.M113.490706. PMID 23897821.
- ↑ 5.0 5.1 "Medicinal chemistry advances in targeting class I histone deacetylases". Exploration of Targeted Anti-Tumor Therapy 4 (4): 757–779. 2023. doi:10.37349/etat.2023.00166. PMID 37711592. PMC 10497394. https://www.explorationpub.com/uploads/Article/A1002166/1002166.pdf#page=17.
- ↑ 6.0 6.1 "Isozyme-selective activity of the HDAC inhibitor MS-275.". Cancer Research (American Association for Cancer Research) 64 (7_Supplement): 567. 1 April 2004. ISSN 0008-5472. https://aacrjournals.org/cancerres/article/64/7_Supplement/567/513901/Isozyme-selective-activity-of-the-HDAC-inhibitor. Retrieved 31 July 2026.
- ↑ 7.0 7.1 "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. May 2023. doi:10.1021/acs.jmedchem.3c00525. PMID 37184921. "Table 6. Inhibitory Activity (IC50) against HDAC Isoforms 1−11 [...]".
- ↑ "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). October 2023. doi:10.1186/s12916-023-03094-0. PMID 37880708.
- ↑ "Phase I trial of 5-azacitidine (5AC) and SNDX-275 in advanced lung cancer (NSCLC).". Journal of Clinical Oncology 26 (15_suppl): 19036–. May 2008. doi:10.1200/jco.2008.26.15_suppl.19036.
- ↑ "The Histone Deacetylase Inhibitor Entinostat/Syndax 275 in Osteosarcoma". Current Advances in Osteosarcoma. Advances in Experimental Medicine and Biology. 1257. 2020. pp. 75–83. doi:10.1007/978-3-030-43032-0_7. ISBN 978-3-030-43031-3.
- ↑ "Targeting cancer epigenetic pathways with small-molecule compounds: Therapeutic efficacy and combination therapies". Pharmacological Research 173. November 2021. doi:10.1016/j.phrs.2021.105702. PMID 34102228.
- ↑ "Inhibition of histone deacetylases attenuates tumor progression and improves immunotherapy in breast cancer". Frontiers in Immunology 14. 2023. doi:10.3389/fimmu.2023.1164514. PMID 36969235. Bibcode: 2023FrIm...1464514L.
- ↑ "Histone deacetylase inhibitor, MS-275, exhibits poor brain penetration: PK studies of [CMS-275 using Positron Emission Tomography"]. ACS Chemical Neuroscience 1 (1): 65–73. 2010. doi:10.1021/cn9000268. PMID 20657706.
- ↑ "Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives". Journal of Medicinal Chemistry 42 (15): 3001–3003. July 1999. doi:10.1021/jm980565u. PMID 10425110.
- ↑ "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. April 1999. doi:10.1073/pnas.96.8.4592. PMID 10200307. Bibcode: 1999PNAS...96.4592S.
- ↑ "Company Prepares for Pivotal Phase 3 Study of Entinostat, Most Advanced HDAC Inhibitor in Development for ER+ Metastatic Breast Cancer". Syndax Pharmaceuticals. 27 August 2013. http://www.syndax.com/assets/130827%20Syndax%20Series%20B%20news%20release.pdf.
- ↑ "Targeting nuclear receptor corepressors for reversible male contraception". Proceedings of the National Academy of Sciences of the United States of America 121 (9). February 2024. doi:10.1073/pnas.2320129121. PMID 38377195. Bibcode: 2024PNAS..12120129H.
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