RGFP966

RGFP966
Clinical data
Other namesRGFP-966
Drug classHistone deacetylase inhibitor; HDAC3 inhibitor; Cognitive enhancer
ATC code
  • None
Identifiers
  • (E)-N-(2-amino-4-fluorophenyl)-3-[1-[(E)-3-phenylprop-2-enyl]pyrazol-4-yl]prop-2-enamide
CAS Number
PubChem CID
ChemSpider
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H19FN4O
Molar mass362.408 g·mol−1
3D model (JSmol)
  • C1=CC=C(C=C1)/C=C/CN2C=C(C=N2)/C=C/C(=O)NC3=C(C=C(C=C3)F)N
  • InChI=1S/C21H19FN4O/c22-18-9-10-20(19(23)13-18)25-21(27)11-8-17-14-24-26(15-17)12-4-7-16-5-2-1-3-6-16/h1-11,13-15H,12,23H2,(H,25,27)/b7-4+,11-8+
  • Key:BLVQHYHDYFTPDV-VCABWLAWSA-N

RGFP966, or RGFP-966, is a histone deacetylase (HDAC) inhibitor which is used in scientific research. It is a highly selective HDAC3 inhibitor. The drug is the most commonly used selective HDAC3 inhibitor in research.

Pharmacology

Pharmacodynamics

RGFP966 activities
EnzymeIC50Tooltip Half-maximal inhibitory concentration (nM)
HDAC15,600–28,670
HDAC23,010–17,680
HDAC380–401
HDAC4>20,000
HDAC5>20,000
HDAC6>20,000
HDAC7>20,000
HDAC8>100,000
HDAC9>20,000
HDAC10>20,000
HDAC11>20,000
Refs:

RGFP966 is a histone deacetylase (HDAC) inhibitor, specifically acting as a highly selective HDAC3 inhibitor, with an IC50Tooltip half-maximal inhibitory concentration of 80 nM and no inhibition of other HDACs at concentrations of up to 15,000 nM or 20,000 nM.

It enhances cognition, memory, and learning in rodents. The drug reverses age-related impairments in memory updating in rodents. In addition, it has been found to facilitate the extinction of drug-seeking behavior in a manner refractory to reinstatement in rodents. Conversely, unlike the pan-class I HDAC inhibitor RGFP963, RGFP966 failed to enhance consolidation of cued fear extinction in rodents, suggesting that HDAC1 and/or HDAC2 may be involved in this instead.

Also unlike pan-class I HDAC inhibitors, which can enhance synaptogenesis, RGFP966 showed minimal effect in this regard. The drug increases brain-derived neurotrophic factor (BDNF) expression. Knockdown of HDAC2 and knockdown of HDAC3 have been found to increase BDNF expression, whereas knockdown of other HDACs did not do so.

RGFP966 produces anti-inflammatory effects. It shows antidepressant-like effects against neuroinflammation-induced depression in rodents. Similarly to butyric acid (butyrate), RGFP966 ameliorates sleep deprivation-induced intestinal mucosa-induced damage in rodents. RGFP966 has neuroprotective and neurorestorative effects in preclinical research.

Pharmacokinetics

The pharmacokinetics of RGFP966 in rodents have been described. It efficiently crosses the blood–brain barrier in rodents.

History

RGFP966 was first described in the scientific literature by 2013.

See also

References

  1. ↑ "Delving into the Latest Updates on RGFP-966 with Synapse". Synapse. 14 March 2026. Retrieved 31 July 2026.
  2. 1 2 3 4 5 6 7 8 9 Malvaez M, McQuown SC, Rogge GA, Astarabadi M, Jacques V, Carreiro S, et al. (February 2013). "HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner". Proceedings of the National Academy of Sciences of the United States of America. 110 (7): 2647–2652. doi:10.1073/pnas.1213364110. PMC 3574934. PMID 23297220. A substrate-dependent biochemical assay using recombinant human HDACs preincubated for 2 h with inhibitor (Reaction Biology) found that RGFP966 is specific for HDAC3, with an IC50 of 0.08 μM and no effective inhibition of any other HDAC at concentrations up to 15 μM.
  3. 1 2 3 4 Bian HT, Xiao L, Liang L, Xie YP, Wang HL, Wang GH (December 2021). "RGFP966 is protective against lipopolysaccharide-induced depressive-like behaviors in mice by inhibiting neuroinflammation and microglial activation". International Immunopharmacology. 101 (Pt B) 108259. doi:10.1016/j.intimp.2021.108259. PMID 34666303.
  4. 1 2 3 4 Bowers ME, Xia B, Carreiro S, Ressler KJ (April 2015). "The Class I HDAC inhibitor RGFP963 enhances consolidation of cued fear extinction". Learning & Memory. 22 (4). Cold Spring Harbor, N.Y.: 225–231. doi:10.1101/lm.036699.114. PMC 4371170. PMID 25776040. RGFP966 and RGFP963 were developed by RepliGen Corp. and sent to Reaction Biology Corp. to determine inhibitory potency against all 11 HDAC enzymes [...] Compounds were tested in 10-dose IC50 mode in duplicate with threefold serial dilution starting at 20 μM [...] RGFP966 and RGFP963 show effective inhibitory potency for the Class I HDAC enzymes (Fig. 1A). RGFP966 exhibited specific inhibition of HDAC3, while RGFP963 broadly inhibited HDAC1, HDAC2, and HDAC3. RGFP963 also showed weak inhibition of HDAC10 with an IC50 value of 10 μM. RGFP963 and RGFP966 did not inhibit any other HDACs besides HDAC1, HDAC2, HDAC3, and HDAC10. [...] Figure 1. RGFP963 and RGFP966 compound properties in vitro and in vivo. (A) RGFP966 exhibits specific inhibition of HDAC3, while RGFP963 broadly inhibits HDAC1, HDAC2, and HDAC3 in vitro. [...]
  5. ↑ Bresciani A, Ontoria JM, Biancofiore I, Cellucci A, Ciammaichella A, Di Marco A, et al. (April 2019). "Improved Selective Class I HDAC and Novel Selective HDAC3 Inhibitors: Beyond Hydroxamic Acids and Benzamides". ACS Medicinal Chemistry Letters. 10 (4): 481–486. doi:10.1021/acsmedchemlett.8b00517. PMC 6466521. PMID 30996783.
  6. 1 2 3 Rumbaugh G, Daws SE, Ozkan ED, Rojas CS, Hubbs CR, Aceti M, et al. (September 2015). "Pharmacological Selectivity Within Class I Histone Deacetylases Predicts Effects on Synaptic Function and Memory Rescue". Neuropsychopharmacology. 40 (10): 2307–2316. doi:10.1038/npp.2015.93. PMC 4538358. PMID 25837283. RGFP966 is 4200-fold more selective for HDAC3 than -1 and -2, with no activity detected at the other HDACs (Supplementary Table S1; Malvaez et al, 2013). [...]
  7. ↑ Stopper D, Biermann L, Watson PR, Li J, König B, Gaynes MN, et al. (February 2025). "Exploring Alternative Zinc-Binding Groups in Histone Deacetylase (HDAC) Inhibitors Uncovers DS-103 as a Potent Ethylhydrazide-Based HDAC Inhibitor with Chemosensitizing Properties". J Med Chem. 68 (4): 4426–4452. doi:10.1021/acs.jmedchem.4c02373. PMC 11867874. PMID 39946728. Table 2. HDAC inhibition by DS-103 compared to known HDAC inhibitors. [...]
  8. 1 2 Leus NG, van der Wouden PE, van den Bosch T, Hooghiemstra WT, Ourailidou ME, Kistemaker LE, et al. (May 2016). "HDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-κB p65 transcriptional activity". Biochemical Pharmacology. 108: 58–74. doi:10.1016/j.bcp.2016.03.010. PMC 4844503. PMID 26993378. As a first step we verified the IC50 values of RGFP966 against the deacetylase activity of recombinant human HDAC 1-3 and 8 [18,19]. RGFP966 potently and selectively inhibited HDAC 3 at nanomolar concentrations, while HDAC 1, 2 and 8 were not inhibited at such concentrations, (Figure 2A) indicating a good level of selectivity for HDAC 3. [...]
  9. ↑ Bieszczad KM, Bechay K, Rusche JR, Jacques V, Kudugunti S, Miao W, et al. (September 2015). "Histone Deacetylase Inhibition via RGFP966 Releases the Brakes on Sensory Cortical Plasticity and the Specificity of Memory Formation". The Journal of Neuroscience. 35 (38): 13124–13132. doi:10.1523/JNEUROSCI.0914-15.2015. PMC 4579377. PMID 26400942.
  10. ↑ Suelves N, Kirkham-McCarthy L, Lahue RS, Ginés S (July 2017). "A selective inhibitor of histone deacetylase 3 prevents cognitive deficits and suppresses striatal CAG repeat expansions in Huntington's disease mice". Scientific Reports. 7 (1) 6082. Bibcode:2017NatSR...7.6082S. doi:10.1038/s41598-017-05125-2. PMC 5519595. PMID 28729730.
  11. ↑ Zhu X, Wang S, Yu L, Jin J, Ye X, Liu Y, et al. (October 2017). "HDAC3 negatively regulates spatial memory in a mouse model of Alzheimer's disease". Aging Cell. 16 (5): 1073–1082. doi:10.1111/acel.12642. PMC 5595690. PMID 28771976.
  12. ↑ Shang A, Bylipudi S, Bieszczad KM (January 2019). "Inhibition of histone deacetylase 3 via RGFP966 facilitates cortical plasticity underlying unusually accurate auditory associative cue memory for excitatory and inhibitory cue-reward associations". Behavioural Brain Research. 356: 453–469. doi:10.1016/j.bbr.2018.05.036. PMID 29860001.
  13. 1 2 3 Sartor GC, Malvezzi AM, Kumar A, Andrade NS, Wiedner HJ, Vilca SJ, et al. (January 2019). "Enhancement of BDNF Expression and Memory by HDAC Inhibition Requires BET Bromodomain Reader Proteins". The Journal of Neuroscience. 39 (4): 612–626. doi:10.1523/JNEUROSCI.1604-18.2018. PMC 6343644. PMID 30504275.
  14. 1 2 Smies CW, Bellfy L, Wright DS, Bennetts SG, Urban MW, Brunswick CA, et al. (2024). "Pharmacological HDAC3 inhibition alters memory updating in young and old male mice". Frontiers in Molecular Neuroscience. 17 1429880. doi:10.3389/fnmol.2024.1429880. PMC 11234845. PMID 38989157.
  15. ↑ Hitchcock LN, Raybuck JD, Wood MA, Lattal KM (January 2019). "Effects of a histone deacetylase 3 inhibitor on extinction and reinstatement of cocaine self-administration in rats". Psychopharmacology. 236 (1). Berl: 517–529. doi:10.1007/s00213-018-5122-2. PMC 6459190. PMID 30488346.
  16. ↑ Louis Sam Titus AS, Sharma D, Kim MS, D'Mello SR (December 2019). "The Bdnf and Npas4 genes are targets of HDAC3-mediated transcriptional repression". BMC Neuroscience. 20 (1) 65. doi:10.1186/s12868-019-0546-0. PMC 6935488. PMID 31883511.
  17. ↑ Zhang H, Ji L, Yang Y, Wei Y, Zhang X, Gang Y, et al. (2019). "The Therapeutic Effects of Treadmill Exercise on Osteoarthritis in Rats by Inhibiting the HDAC3/NF-KappaB Pathway in vivo and in vitro". Frontiers in Physiology. 10 1060. doi:10.3389/fphys.2019.01060. PMC 6710443. PMID 31481898.
  18. ↑ Ren L, Jia A, Ren M, Lu G, Feng Y, He S (September 2019). "[Histone deacetylase 3 inhibitor alleviates alcohol-induced disruption of intestinal epithelial barrier via inhibiting nuclear factor κB]". Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi = Chinese Journal of Cellular and Molecular Immunology (in Chinese). 35 (9): 800–805. PMID 31750821.
  19. 1 2 Zhang MJ, Zhao QC, Xia MX, Chen J, Chen YT, Cao X, et al. (January 2020). "The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome". FASEB Journal. 34 (1): 648–662. doi:10.1096/fj.201900394RRR. PMID 31914678.
  20. ↑ Zhang W, Sun X, Ba G, Tang R, Lin H (April 2021). "RGFP966, a selective HDAC3 inhibitor, ameliorates allergic and inflammatory responses in an OVA-induced allergic rhinitis mouse model". International Immunopharmacology. 93 107400. doi:10.1016/j.intimp.2021.107400. PMID 33529911.
  21. ↑ Cai M, Shao H, Xu S, Wang H, Yang MJ, Zhu T, et al. (January 2026). "HDAC3 Mediates Hippocampal Microglial Pyroptosis Via the STING/NLRP3 Pathway and Contributes To Cognitive Impairment in Sepsis-Associated Encephalopathy". Inflammation. 49 (1) 39. doi:10.1007/s10753-025-02360-y. PMC 12858564. PMID 41518423.
  22. ↑ Gao T, Wang Z, Dong Y, Cao J, Chen Y (February 2023). "Butyrate Ameliorates Insufficient Sleep-Induced Intestinal Mucosal Damage in Humans and Mice". Microbiology Spectrum. 11 (1) e02000-22: e0200022. doi:10.1128/spectrum.02000-22. PMC 9927315. PMID 36541814.
  23. ↑ Matheson R, Chida K, Lu H, Clendaniel V, Fisher M, Thomas A, et al. (October 2020). "Neuroprotective Effects of Selective Inhibition of Histone Deacetylase 3 in Experimental Stroke". Translational Stroke Research. 11 (5): 1052–1063. doi:10.1007/s12975-020-00783-3. PMID 32016769.
  24. ↑ Gu HP, Wu XF, Gong YT, Wu MY, Shi MY, Sun YM, et al. (July 2023). "RGFP966 exerts neuroprotective effect via HDAC3/Nrf2 pathway after surgical brain injury in rats". Heliyon. 9 (7) e18160. Bibcode:2023Heliy...918160G. doi:10.1016/j.heliyon.2023.e18160. PMC 10395478. PMID 37539293.
  25. ↑ Wang J, Yang M, Chen Y, Liu Y, Zhang H, Tian R, et al. (October 2023). "HDAC3 Contributes to Ischemic Stroke by Regulating Interferon Pathway". Journal of Integrative Neuroscience. 22 (6) 156. doi:10.31083/j.jin2206156. PMID 38176919.
  26. ↑ Keiser AA, Kramár EA, Dong T, Shanur S, Pirodan M, Ru N, et al. (February 2021). "Systemic HDAC3 inhibition ameliorates impairments in synaptic plasticity caused by simulated galactic cosmic radiation exposure in male mice". Neurobiology of Learning and Memory. 178 107367. Bibcode:2021NeuLM.17807367K. doi:10.1016/j.nlm.2020.107367. PMC 8456980. PMID 33359392.
  27. ↑ Xu L, An T, Jia B, Wu Q, Shen J, Jin J, et al. (2024). "Histone deacetylase 3-specific inhibitor RGFP966 attenuates oxidative stress and inflammation after traumatic brain injury by activating the Nrf2 pathway". Burns & Trauma. 12 tkad062. doi:10.1093/burnst/tkad062. PMC 11069425. PMID 38708192.