Chemistry:Tacedinaline

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Tacedinaline (INN, USAN; developmental code name CI-994), also known as N-acetyldinaline, is a histone deacetylase (HDAC) inhibitor and possible cognitive enhancer which is under development for the treatment of Alzheimer's disease.[1][2][3] It was also under development as an antineoplastic agent for the treatment of various cancers, but development for these uses was discontinued.[1][4] The drug is taken orally.[1]

Side effects

Unlike many other less-selective HDAC inhibitors, which have often produced unwanted side effects, tacedinaline is said to be well-tolerated.[2] However, adverse effects such as thrombocytopenia among others have nonetheless been observed in cancer treatment trials.[5][6][7][8]

Pharmacology

Tacedinaline activities
Enzyme IC50 (nM)
HDAC1 41–636
HDAC2 147–696
HDAC3 46–472
HDAC4 >33,000
HDAC5 >33,000
HDAC6 >33,000
HDAC7 >33,000
HDAC8 >33,000
HDAC9 >33,000
HDAC10 >10,000
HDAC11 >10,000
Refs: [2][9][10]

Tacedinaline is a potent inhibitor of the class I HDAC1, HDAC2, and HDAC3, with IC50 values of 41–636 nM, 147–696 nM, and 46–472 nM, respectively.[2][9][10] The drug showed no inhibition of other HDACs, including HDAC4 through HDAC11, at a concentration of 10,000 to 33,000 nM.[2][9][10] It is more selective for class I HDACs compared to many other HDAC inhibitors.[2] In addition to its HDAC inhibition, tacedinaline also activates Wnt/β–catenin signaling and hence is said to have a dual mechanism of action.[2] It enhances synaptogenesis, increases central brain-derived neurotrophic factor (BDNF) expression, and decreases tau phosphorylation in preclinical research.[11][2] Tacedinaline enhances cognition and memory in rodents.[2][12][13][14] It crosses the blood–brain barrier.[2][15] The drug's time to peak levels is approximately 1 to 2 hours and elimination half-life is 9.6 to 14 hours in humans.[16][5][7][17]

Chemistry

The chemical synthesis of tacedinaline has been described.[18] Glucuronide prodrugs of tacedinaline for targeted tumor chemotherapy have been described.[19]

History and development

Tacedinaline was first described in the scientific literature by 1993.[20] It was developed by Goedecke and Pfizer.[1] As of September 2024, the drug is in the preclinical research stage of development for Alzheimer's disease.[1] It was also under development for the treatment of breast cancer, colorectal cancer, lung cancer, and pancreatic cancer, and reached phase 2 and 3 trials for these uses in the 2000s, but development was discontinued by 2008.[1][4] Subsequently, tacedinaline was repurposed for the treatment of Alzheimer's disease in the 2020s.[1][2][3]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Tacedinaline". 27 September 2024. https://adisinsight.springer.com/drugs/800002525. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 "CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease". Alzheimer's Research & Therapy 18 (1). February 2026. doi:10.1186/s13195-026-01982-0. PMID 41654970. "We demonstrated that CI-994 greatly increased Wnt reporter activity in Wnt-3A-expressing HEK293 cells with an EC50 value around 5.8 µM (Fig. 1B) and inhibited class I HDAC1, 2 and 3 activities with IC50 values of 617 nM, 593 nM and 472 nM, respectively (Fig. 1C). [...] As expected, CI-994 at 10 µM has no inhibitory effects on other HDACs (Table 1).". 
  3. ↑ 3.0 3.1 "Discovery of a CI-994 derivative as a dual modulator of class I histone deacetylases and Wnt/β-catenin signaling for Alzheimer's disease therapy". Neurotherapeutics 23 (5). July 2026. doi:10.1016/j.neurot.2026.e00974. PMID 42508295. 
  4. ↑ 4.0 4.1 "The potential role of histone deacetylase inhibitors in the treatment of non-small-cell lung cancer". Critical Reviews in Oncology/Hematology 68 (1): 29–36. October 2008. doi:10.1016/j.critrevonc.2008.03.002. PMID 18424067. 
  5. ↑ 5.0 5.1 "Chronic oral administration of CI-994: a phase 1 study". Investigational New Drugs 19 (1): 1–11. 2001. doi:10.1023/a:1006489328324. PMID 11291827. 
  6. ↑ "Phase I study of oral CI-994 in combination with gemcitabine in treatment of patients with advanced cancer". Cancer Journal (Sudbury, Mass.) 9 (1): 58–66. 2003. doi:10.1097/00130404-200301000-00010. PMID 12602769. 
  7. ↑ 7.0 7.1 "A phase I study of the oral combination of CI-994, a putative histone deacetylase inhibitor, and capecitabine". Annals of Oncology 15 (11): 1705–1711. November 2004. doi:10.1093/annonc/mdh438. PMID 15520075. 
  8. ↑ "Phase I study of oral CI-994 in combination with carboplatin and paclitaxel in the treatment of patients with advanced solid tumors". Cancer Investigation 22 (6): 886–896. 2004. doi:10.1081/cnv-200039852. PMID 15641487. 
  9. ↑ 9.0 9.1 9.2 "Balancing Histone Deacetylase (HDAC) Inhibition and Drug-likeness: Biological and Physicochemical Evaluation of Class I Selective HDAC Inhibitors". ChemMedChem 17 (9). May 2022. doi:10.1002/cmdc.202100755. PMID 35073610. 
  10. ↑ 10.0 10.1 10.2 "FDG-PET imaging reveals local brain glucose utilization is altered by class I histone deacetylase inhibitors". Neurosci Lett 550: 119–124. August 2013. doi:10.1016/j.neulet.2013.06.016. PMID 23810801. 
  11. ↑ "Inhibition of HDAC increases BDNF expression and promotes neuronal rewiring and functional recovery after brain injury". Cell Death & Disease 11 (8). August 2020. doi:10.1038/s41419-020-02897-w. PMID 32811822. 
  12. ↑ "The HDAC inhibitor CI-994 acts as a molecular memory aid by facilitating synaptic and intracellular communication after learning". Proceedings of the National Academy of Sciences of the United States of America 119 (22). May 2022. doi:10.1073/pnas.2116797119. PMID 35613054. Bibcode: 2022PNAS..11916797B. 
  13. ↑ "Class I histone deacetylase (HDAC) inhibitor CI-994 promotes functional recovery following spinal cord injury". Cell Death & Disease 9 (5). May 2018. doi:10.1038/s41419-018-0543-8. PMID 29700327. 
  14. ↑ "Dose Effects of Histone Deacetylase Inhibitor Tacedinaline (CI-994) on Antipsychotic Haloperidol-Induced Motor and Memory Side Effects in Aged Mice". Frontiers in Neuroscience 15. 2021. doi:10.3389/fnins.2021.674745. PMID 34690667. 
  15. ↑ "Pharmacokinetics and cerebrospinal fluid penetration of CI-994 (N-acetyldinaline) in the nonhuman primate". Clinical Cancer Research 6 (3): 994–997. March 2000. PMID 10741726. 
  16. ↑ "Tacedinaline". 5 February 2010. https://drugs.ncats.io/drug/UMF554N5FG. 
  17. ↑ Merriman RL, Klohs WD, "Combination chemotherapy", WO patent 2001034131, published 3 November 2000, assigned to Warner Lambert Co LLC
  18. ↑ "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". Bioorganic & Medicinal Chemistry 16 (6): 3352–3360. March 2008. doi:10.1016/j.bmc.2007.12.007. PMID 18166465. 
  19. ↑ "Synthesis and biological evaluation of glucuronide prodrugs of the histone deacetylase inhibitor CI-994 for application in selective cancer chemotherapy". Bioorganic & Medicinal Chemistry 16 (17): 8109–8116. September 2008. doi:10.1016/j.bmc.2008.07.048. PMID 18692397. 
  20. ↑ "Acetyldinaline: a new oral cytostatic drug with impressive differential activity against leukemic cells and normal stem cells--preclinical studies in a relevant rat model for human acute myelocytic leukemia". Cancer Research 53 (13): 3008–3014. July 1993. PMID 8319208. 



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