C22 H19 F N4 O2
Benzamide, N-(2-amino-4-fluorophenyl)-4-(((1-oxo-3-(3-pyridinyl)-2-propen-1-yl)amino)methyl)-Benzamide, N-(2-amino-4-fluorophenyl)-4-((((2E)-1-oxo-3-(3-pyridinyl)-2-propen-1-yl)amino)methyl)-
Tucidinostat is in Phase 2/3 development as a latency-reversing agent for HIV.
Molecular Weight: 390.4161
(Compound details obtained from ChemIDplus Advanced,1 HUYA Bioscience International website,2 and Treatment Action Group website3)
Mechanism of Action: Latency-reversing agent, specifically a histone deacetylase inhibitor (HDACi).3 Tucidinostat, a benzamide derivative, is an HDACi that selectively targets the class I HDAC enzymes HDAC-1, -2, and -3, which are important in the disruption of HIV latency.Additionally, tucidinostat is active against the class II HDAC-10 enzyme.4,5 Tucidinostat has also been shown to reactivate latent HIV via the NF-κB signaling pathway.6 Currently, tucidinostat is approved for use in China for the treatment of peripheral T-cell lymphoma and breast cancer.7
In HIV-1 latency, HDACs are recruited to the proviral 5' long terminal repeat (LTR), where they catalyze deacetylation of lysine residues on histones, resulting in chromatin condensation on nucleosome 1 (nuc-1) and preventing HIV transcription. Inhibition of HDAC activity promotes histone acetylation (hyperacetylation) of lysine residues by histone acetyltransferases (HATs), leading to chromatin relaxation and transcriptional activation.5,8 Some research suggests that the activity of HDACis in inducing HIV transcription may not be caused by direct effects on histone acetylation, but may be caused by effects on other non-histone proteins.9,10
Half-life (T1/2): In a Phase 1b/2a trial (NCT02513901) of tucidinostat in adults with HIV, the elimination half-life of tucidinostat after a single oral 10-mg dose was approximately 11.5 hours. After multiple oral 10-mg doses of tucidinostat, the half-life was approximately 15.5 hours.11
Select Clinical Trials
Study Identifiers: CHARTER; NCT02513901
Sponsor: Tang-Du Hospital
Status: This study has been completed.
Study Purpose: The purpose of this open-label trial was to evaluate the safety of tucidinostat plus ART and the efficacy of tucidinostat plus ART in reactivating HIV transcription in latently infected cells and reducing latent HIV reservoir size.
- Participants were adults with HIV who were on ART and who had been receiving ART for at least 18 months.
- Participants had HIV RNA <50 copies/mL for at least 1 year and had CD4 counts >350 cells/mm3.11,12
- AIDS, 2018: Chidamide disrupts and reduces HIV-1 latency in patients on suppressive antiretroviral therapy
Study Identifiers: NCT02902185
Sponsor: Tang-Du Hospital
Status: This study has been completed.
Study Purpose: The purpose of this study was to confirm the efficacy of tucidinostat plus ART in reactivating HIV transcription in latently infected cells and reducing latent HIV reservoir size.
- Participants are adults with HIV who are currently on ART and have been receiving ART for at least 24 months.
- Participants have had HIV RNA <20 copies/mL for at least 1.5 years and have CD4 counts >350 cells/mm3.3,13
In this Phase 1b/2a trial, seven participants completed treatment with eight oral doses of tucidinostat. No significant adverse events (AEs) occurred, and all AEs were of Grade 1 severity. Rash and fatigue/somnolence were each reported in one participant. A small decrease in complete blood cell counts, most notably red blood cell counts and hemoglobin values, were seen with tucidinostat treatment, but these cases were all below Grade 1 and returned to baseline levels by Day 56. CD4 counts remained unchanged throughout the study.11,15
Information about drug-drug interactions between tucidinostat and HIV-related drugs is currently unavailable.
- United States National Library of Medicine. ChemIDplus Advanced: tucidinostat. https://chem.nlm.nih.gov/chemidplus/rn/1616493-44-7. Accessed July 13, 2020
- Huya Bioscience International: Press Release, dated March 6, 2007. HUYA Bioscience licenses chidamide cancer compound from Chipscreen Biosciences. https://www.huyabio.com/huya-bioscience-licenses-chidamide-cancer-compound-chipscreen-biosciences/. Accessed July 13, 2020
- Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed July 13, 2020
- Lu X, Ning Z, Li Z, Cao H, Wang X. Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in China. Intractable Rare Dis Res. 2016;5(3):185-191. doi:10.5582/irdr.2016.01024
- Matalon S, Rasmussen TA, Dinarello CA. Histone deacetylase inhibitors for purging HIV-1 from the latent reservoir. Mol Med. 2011;17(5-6):466-472. doi:10.2119/molmed.2011.00076
- Yang W, Sun Z, Hua C, et al. Chidamide, a histone deacetylase inhibitor-based anticancer drug, effectively reactivates latent HIV-1 provirus. Microbes Infect. 2018;20(9-10):626-634. doi:10.1016/j.micinf.2017.10.003
- Shenzhen Chipscreen Biosciences Co., Ltd.: Press Release, dated December 3, 2019. (NMPA) approves Chipscreen Bioscience’s Chidamide (Epidaza) for breast cancer indication. http://www.chipscreen.com/en/index.php/show-626.html. Accessed July 13, 2020
- Rasmussen TA, Tolstrup M, Winckelmann A, Østergaard L, Søgaard OS. Eliminating the latent HIV reservoir by reactivation strategies. Hum Vaccin Immunother. 2013;9(4):790–799.
- Shirakawa K, Chavez L, Hakre S, Calvanese V, Verdin E. Reactivation of latent HIV by histone deacetylase inhibitors. Trends Microbiol. 2013;21(6):277-285. doi:10.1016/j.tim.2013.02.005
- Elliott JH, Wightman F, Solomon A, et al. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog. 2014;10(11). doi:10.1371/journal.ppat.1004473
- Sun Y, Li J, Ma C. Chidamide disrupts and reduces HIV-1 latency in patients on suppressive antiretroviral therapy. Slides presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands. https://programme.aids2018.org/PAGMaterial/PPT/3643_2431/2018-IAS-Chidamide.pptx. Accessed July 13, 2020
- Tang-Du Hospital. Safety and efficacy of the histone deacetylase inhibitor chidamide in combination with antiretroviral therapy for eradication of the latent HIV-1 reservoir (CHARTER). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 30, 2015. NLM Identifier: NCT02513901. https://clinicaltrials.gov/ct2/show/NCT02513901. Accessed July 13, 2020
- Tang-Du Hospital. Efficacy of the histone deacetylase inhibitor chidamide in combination with antiretroviral therapy for reactivation of the latent HIV-1 reservoir: a randomized controlled clinical trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 6, 2016. NLM Identifier: NCT02902185. https://clinicaltrials.gov/ct2/show/NCT02902185. Accessed July 13, 2020
- Guangzhou 8th People’s Hospital. Effect of chidamide combined with CAT-T or TCR-T cell therapy on HIV-1 latent reservoir. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 7, 2019. NLM Identifier: NCT03980691. https://clinicaltrials.gov/ct2/show/NCT03980691. Accessed July 13, 2020
- Sun Y, Li J, Ma J. Chidamide reactivates and diminishes latent HIV-1 DNA in patients on suppressive antiretroviral therapy. Abstract presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands. Abstract WEAA0101. http://programme.aids2018.org/Abstract/Abstract/9294. Accessed July 13, 2020
Last Reviewed: July 13, 2020