Tacedinaline

Tacedinaline

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
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.[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]

Side effects

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][10]

Pharmacology

Tacedinaline activities
Enzyme IC50Tooltip Half-maximal inhibitory concentration (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: [7][11][12]

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.[7][11][12] The drug showed no inhibition of other HDACs, including HDAC4 through HDAC11, at a concentration of 10,000 to 33,000 nM.[7][11][12] 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.[13][7] Tacedinaline enhances cognition and memory in rodents.[7][14][15][16] It crosses the blood–brain barrier.[7][17] 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]

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][9] Subsequently, tacedinaline was repurposed for the treatment of Alzheimer's disease in the 2020s.[1][7][8]

See also

References

  1. ^ a b c d e f g h "Tacedinaline". AdisInsight. 27 September 2024. Retrieved 31 July 2026.
  2. ^ a b WO 2001034131, Merriman RL, Klohs WD, "Combination chemotherapy", published 3 November 2000, assigned to Warner Lambert Co LLC 
  3. ^ a b 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. ^ a b "Tacedinaline". Inxight Drugs. 5 February 2010. Retrieved 31 July 2026.
  5. ^ a b c 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. ^ a b c 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. ^ a b c d e f g h i j k 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. ^ a b 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. ^ a b 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. ^ a b c 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. ^ a b c 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.

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