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Tacedinaline

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Tacedinaline
Clinical data
Other namesAcetyldinaline; N-Acetyldinaline; CI-994; CI994; PD-123654; PD123654; PD-123,654; GOE-5549; GOE5549
Routes of
administration		Oral[1]
Drug classHistone deacetylase inhibitor; Antineoplastic agent; Cognitive enhancer
Pharmacokinetic data
Onset of action1–2 hours (TmaxTooltip time to peak levels)[2][3]
Elimination half-life9.6–14 hours[4][5][6]
Identifiers
  • 4-acetamido-N-(2-aminophenyl)benzamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
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.[1][7][8] It was also under development as an antineoplastic agent for the treatment of various cancers, but development for these uses was discontinued.[1][9] The drug is taken orally.[1]

Tacedinaline activities
EnzymeIC50Tooltip Half-maximal inhibitory concentration (nM)
HDAC1617–636
HDAC2593–696
HDAC3263–472
HDAC4>10,000
HDAC5>10,000
HDAC6>10,000
HDAC7>10,000
HDAC8>10,000
HDAC9>10,000
HDAC10>10,000
HDAC11>10,000
Refs: [7][10]

It is a potent inhibitor of the class I HDAC1, HDAC2, and HDAC3, with IC50Tooltip half-maximal inhibitory concentration values of 617–636 nM, 593–696 nM, and 263–472 nM, respectively.[7][10] The drug showed no inhibition of other HDACs, including HDAC4 through HDAC11, at a concentration of 10,000 nM.[7][10] It is more selective for class I HDACs compared to many other HDAC inhibitors.[7] In addition to its HDAC inhibition, tacedinaline also activates Wnt/β–catenin signaling and hence is said to have a dual mechanism of action.[7] It enhances synaptogenesis, increases central brain-derived neurotrophic factor (BDNF) expression, and decreases tau phosphorylation in preclinical research.[11][7] Tacedinaline enhances cognition and memory in rodents.[7][12][13][14] It crosses the blood–brain barrier.[7][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.[4][5][6][2]

The chemical synthesis of tacedinaline has been described.[16] Glucuronide prodrugs of tacedinaline for targeted tumor chemotherapy have been described.[17]

Tacedinaline was first described in the scientific literature by 1993.[18] 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][9] Subsequently, tacedinaline was repurposed for the treatment of Alzheimer's disease in the 2020s.[1][7][8] Unlike many other less selective HDAC inhibitors, which have often produced unwanted side effects, tacedinaline is said to be well-tolerated.[7] However, adverse effects such as thrombocytopenia among others have nonetheless been observed in cancer treatment trials.[5][3][6][19]

See also

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References

[edit]
  1. 1 2 3 4 5 6 7 8 "Tacedinaline". AdisInsight. 27 September 2024. Retrieved 31 July 2026.
  2. 1 2 "Combination chemotherapy". Google Patents. 3 November 2000. Retrieved 31 July 2026. Preliminary results indicate that the maximum blood level is achieved approximately 1 to 2 hours after ingestion, and the terminal elimination half-life of CI-994 is approximately 15 hours. The maximum plasma CI-994 concentrations achieved with increasing dose levels were less than dose- proportional. The terminal elimination half-life and the apparent clearance rate were independent of the dose administered. [...] Animal studies indicate that the principal route of elimination is via renal excretion, with 80% and 62% of radiolabeled drug appearing in the urine of monkeys and rats, respectively, within 24 hours.
  3. 1 2 Nemunaitis JJ, Orr D, Eager R, Cunningham CC, Williams A, Mennel R, Grove W, Olson S (2003). "Phase I study of oral CI-994 in combination with gemcitabine in treatment of patients with advanced cancer". Cancer J. 9 (1): 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, Zalupski M, Radulovic L, Valdivieso M, LoRusso PM (2001). "Chronic oral administration of CI-994: a phase 1 study". Invest 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, Kimmel KA, Macek TA, Ratain MJ (November 2004). "A phase I study of the oral combination of CI-994, a putative histone deacetylase inhibitor, and capecitabine". Ann Oncol. 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, Lee E, Martinez PR, Izhar T, Wang N, Raulin AC, Wszolek ZK, Bu G, Kanekiyo T, Li Y (February 2026). "CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease". Alzheimers Res Ther. 18 (1). doi:10.1186/s13195-026-01982-0. PMC 12977471. PMID 41654970.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. 1 2 Lu W, Caulfield TR, Lee E, Jeevaratnam S, Wang N, Bu G, Kanekiyo T, Li Y (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. PMID 42508295.{{cite journal}}: CS1 maint: article number as page number (link)
  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". Crit Rev Oncol Hematol. 68 (1): 29–36. doi:10.1016/j.critrevonc.2008.03.002. PMID 18424067.
  10. 1 2 3 Schäker-Hübner L, Haschemi R, Büch T, Kraft FB, Brumme B, Schöler A, Jenke R, Meiler J, Aigner A, Bendas G, Hansen FK (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.{{cite journal}}: CS1 maint: article number as page number (link)
  11. ↑ 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 Dis. 11 (8): 655. doi:10.1038/s41419-020-02897-w. PMC 7434917. PMID 32811822.
  12. ↑ 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". Proc Natl Acad Sci U S A. 119 (22): e2116797119. doi:10.1073/pnas.2116797119. PMC 9295763. PMID 35613054.{{cite journal}}: CS1 maint: article number as page number (link)
  13. ↑ 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 Dis. 9 (5): 460. doi:10.1038/s41419-018-0543-8. PMC 5919919. PMID 29700327.
  14. ↑ 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". Front Neurosci. 15: 674745. doi:10.3389/fnins.2021.674745. PMC 8526546. PMID 34690667.{{cite journal}}: CS1 maint: article number as page number (link) CS1 maint: unflagged free DOI (link)
  15. ↑ Riva L, Blaney SM, Dauser R, Nuchtern JG, Durfee J, McGuffey L, Berg SL (March 2000). "Pharmacokinetics and cerebrospinal fluid penetration of CI-994 (N-acetyldinaline) in the nonhuman primate". Clin Cancer Res. 6 (3): 994–997. PMID 10741726.
  16. ↑ 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". Bioorg Med Chem. 16 (6): 3352–3360. doi:10.1016/j.bmc.2007.12.007. PMC 2374748. PMID 18166465.
  17. ↑ 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". Bioorg Med Chem. 16 (17): 8109–8116. doi:10.1016/j.bmc.2008.07.048. PMID 18692397.
  18. ↑ 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 Res. 53 (13): 3008–3014. PMID 8319208.
  19. ↑ Pauer LR, Olivares J, Cunningham C, Williams A, Grove W, Kraker A, Olson S, Nemunaitis J (2004). "Phase I study of oral CI-994 in combination with carboplatin and paclitaxel in the treatment of patients with advanced solid tumors". Cancer Invest. 22 (6): 886–896. doi:10.1081/cnv-200039852. PMID 15641487.
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