Tacedinaline

Tacedinaline
Clinical data
Other namesAcetyldinaline; N-Acetyldinaline; CI-994; CI994; PD-123654; PD123654; PD-123,654; GOE-5549; GOE5549
Routes of
administration		Oral
Drug classHistone deacetylase inhibitor; Antineoplastic agent; Cognitive enhancer
Pharmacokinetic data
Onset of action1–2 hours (TmaxTooltip time to peak levels)
Elimination half-life9.6–14 hours
Identifiers
  • 4-acetamido-N-(2-aminophenyl)benzamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.159.485 Edit this at Wikidata
Chemical and physical data
FormulaC15H15N3O2
Molar mass269.304 g·mol−1
3D model (JSmol)
  • CC(=O)NC1=CC=C(C=C1)C(=O)NC2=CC=CC=C2N
  • InChI=1S/C15H15N3O2/c1-10(19)17-12-8-6-11(7-9-12)15(20)18-14-5-3-2-4-13(14)16/h2-9H,16H2,1H3,(H,17,19)(H,18,20)
  • Key:VAZAPHZUAVEOMC-UHFFFAOYSA-N

Tacedinaline (INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name; 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. It was also under development as an antineoplastic agent for the treatment of various cancers, but development for these uses was discontinued. The drug is taken orally.

Side effects

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

Pharmacology

Tacedinaline activities
EnzymeIC50Tooltip Half-maximal inhibitory concentration (nM)
HDAC141–636
HDAC2147–696
HDAC346–472
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:

Tacedinaline is a potent inhibitor of the class I HDAC1, HDAC2, and HDAC3, with IC50Tooltip half-maximal inhibitory concentration values of 41–636 nM, 147–696 nM, and 46–472 nM, respectively. The drug showed no inhibition of other HDACs, including HDAC4 through HDAC11, at a concentration of 10,000 to 33,000 nM. It is more selective for class I HDACs compared to many other HDAC inhibitors. In addition to its HDAC inhibition, tacedinaline also activates Wnt/β–catenin signaling and hence is said to have a dual mechanism of action. It enhances synaptogenesis, increases central brain-derived neurotrophic factor (BDNF) expression, and decreases tau phosphorylation in preclinical research. Tacedinaline enhances cognition and memory in rodents. It crosses the blood–brain barrier. 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.

Chemistry

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

History and development

Tacedinaline was first described in the scientific literature by 1993. It was developed by Goedecke and Pfizer. As of September 2024, the drug is in the preclinical research stage of development for Alzheimer's disease. 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. Subsequently, tacedinaline was repurposed for the treatment of Alzheimer's disease in the 2020s.

See also

References

  1. 1 2 3 4 5 6 7 8 "Tacedinaline". AdisInsight. 27 September 2024. Retrieved 31 July 2026.
  2. 1 2 WO 2001034131, Merriman RL, Klohs WD, "Combination chemotherapy", published 3 November 2000, assigned to Warner Lambert Co LLC
  3. 1 2 Nemunaitis JJ, Orr D, Eager R, Cunningham CC, Williams A, Mennel R, et al. (2003). "Phase I study of oral CI-994 in combination with gemcitabine in treatment of patients with advanced cancer". Cancer Journal. 9 (1). Sudbury, Mass.: 58–66. doi:10.1097/00130404-200301000-00010. PMID 12602769.
  4. 1 2 "Tacedinaline". Inxight Drugs. 5 February 2010. Retrieved 31 July 2026.
  5. 1 2 3 Prakash S, Foster BJ, Meyer M, Wozniak A, Heilbrun LK, Flaherty L, et al. (2001). "Chronic oral administration of CI-994: a phase 1 study". Investigational New Drugs. 19 (1): 1–11. doi:10.1023/a:1006489328324. PMID 11291827.
  6. 1 2 3 Undevia SD, Kindler HL, Janisch L, Olson SC, Schilsky RL, Vogelzang NJ, et al. (November 2004). "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. doi:10.1093/annonc/mdh438. PMID 15520075.
  7. 1 2 3 4 5 6 7 8 9 10 11 Lu W, Kawatani K, Ren Y, Nambara T, Jia L, Jeevaratnam S, et al. (February 2026). "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) 60. doi:10.1186/s13195-026-01982-0. PMC 12977471. 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).
  8. 1 2 Lu W, Caulfield TR, Lee E, Jeevaratnam S, Wang N, Bu G, et al. (July 2026). "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) e00974. doi:10.1016/j.neurot.2026.e00974. PMC 13445382. PMID 42508295.
  9. 1 2 Gridelli C, Rossi A, Maione P (October 2008). "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. doi:10.1016/j.critrevonc.2008.03.002. PMID 18424067.
  10. ↑ Pauer LR, Olivares J, Cunningham C, Williams A, Grove W, Kraker A, et al. (2004). "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. doi:10.1081/cnv-200039852. PMID 15641487.
  11. 1 2 3 Schäker-Hübner L, Haschemi R, Büch T, Kraft FB, Brumme B, Schöler A, et al. (May 2022). "Balancing Histone Deacetylase (HDAC) Inhibition and Drug-likeness: Biological and Physicochemical Evaluation of Class I Selective HDAC Inhibitors". ChemMedChem. 17 (9) e202100755. doi:10.1002/cmdc.202100755. PMC 9303312. PMID 35073610.
  12. 1 2 3 Schroeder FA, Chonde DB, Riley MM, Moseley CK, Granda ML, Wilson CM, et al. (August 2013). "FDG-PET imaging reveals local brain glucose utilization is altered by class I histone deacetylase inhibitors". Neurosci Lett. 550: 119–124. doi:10.1016/j.neulet.2013.06.016. PMC 3750730. PMID 23810801.
  13. ↑ Sada N, Fujita Y, Mizuta N, Ueno M, Furukawa T, Yamashita T (August 2020). "Inhibition of HDAC increases BDNF expression and promotes neuronal rewiring and functional recovery after brain injury". Cell Death & Disease. 11 (8) 655. doi:10.1038/s41419-020-02897-w. PMC 7434917. PMID 32811822.
  14. ↑ Burns AM, Farinelli-Scharly M, Hugues-Ascery S, Sanchez-Mut JV, Santoni G, Gräff J (May 2022). "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) e2116797119. Bibcode:2022PNAS..11916797B. doi:10.1073/pnas.2116797119. PMC 9295763. PMID 35613054.
  15. ↑ Zhang S, Fujita Y, Matsuzaki R, Yamashita T (May 2018). "Class I histone deacetylase (HDAC) inhibitor CI-994 promotes functional recovery following spinal cord injury". Cell Death & Disease. 9 (5) 460. doi:10.1038/s41419-018-0543-8. PMC 5919919. PMID 29700327.
  16. ↑ McClarty B, Rodriguez G, Dong H (2021). "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 674745. doi:10.3389/fnins.2021.674745. PMC 8526546. PMID 34690667.
  17. ↑ Riva L, Blaney SM, Dauser R, Nuchtern JG, Durfee J, McGuffey L, et al. (March 2000). "Pharmacokinetics and cerebrospinal fluid penetration of CI-994 (N-acetyldinaline) in the nonhuman primate". Clinical Cancer Research. 6 (3): 994–997. PMID 10741726.
  18. ↑ Gediya LK, Belosay A, Khandelwal A, Purushottamachar P, Njar VC (March 2008). "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. doi:10.1016/j.bmc.2007.12.007. PMC 2374748. PMID 18166465.
  19. ↑ Thomas M, Clarhaut J, Tranoy-Opalinski I, Gesson JP, Roche J, Papot S (September 2008). "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. doi:10.1016/j.bmc.2008.07.048. PMID 18692397.
  20. ↑ el-Beltagi HM, Martens AC, Lelieveld P, Haroun EA, Hagenbeek A (July 1993). "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. PMID 8319208.