Tacedinaline (, ; 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 + Enzyme (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:
Tacedinaline is a potent inhibitor of the class I HDAC1, HDAC2, and HDAC3, with values of 41–636nM, 147–696nM, and 46–472nM, respectively. The drug showed no inhibition of other HDACs, including HDAC4 through HDAC11, at a concentration of 10,000 to 33,000nM. 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 2hours and elimination half-life is 9.6 to 14hours 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 Histone deacetylase inhibitor BRD-6929 (Cpd-60) FRM-0334 (EVP-0334)
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