Chemistry:BRD-6929

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BRD-6929, also widely known as "compound 60" (Cpd-60 or Cmpd60), is a histone deacetylase (HDAC) inhibitor which is used in scientific research.[1][2][3][4] It has been described in the past as the prototypical selective HDAC1 and HDAC2 inhibitor.[5][6] However, subsequent findings suggest that BRD-6929 may not actually be selective for HDAC1 and HDAC2 over HDAC3.[1][6]

Pharmacology

Pharmacodynamics

BRD-6929 activities
Enzyme IC50 (nM)
HDAC1 1
HDAC2 8–13
HDAC3 398–458
HDAC4 >33,000
HDAC5 >33,000
HDAC6 >33,000
HDAC7 >33,000
HDAC8 >33,000
HDAC9 >33,000
HDAC10 3,400
Refs: [2][3][4][7]

BRD-6929 is a selective inhibitor of HDAC1 and HDAC2, with IC50 values of 1 nM and 8–30 nM, respectively, and with 30- to 400-fold selectivity over HDAC3 (IC50 = 398–458 nM) and no inhibition of HDAC8 or class II HDACs (IC50 = >30,000 nM).[2][3][4] However, although originally reported to be selective for inhibition of HDAC1 and HDAC2 over HDAC3, subsequent research has found that BRD-6929 is not in fact selective over HDAC3, with previous findings being claimed to have been an assay artifact.[1][6] As a result, BRD-6929 is no longer recommended as a selective HDAC1 and HDAC2 inhibitor.[1] The drug shows slow-on/slow-off binding kinetics and hence more sustained HDAC inhibition, unlike other HDAC inhibitors like the fast-on/fast-off vorinostat (SAHA) and entinostat (MS-275).[3] Aside from the HDACs, it also showed no binding at 80 other targets at a concentration of 10,000 nM.[3]

BRD-6929 produces antidepressant-like and mood-stabilizing-like effects in rodents.[3][8][9] This included reducing immobility in the forced swim test (FST) and attenuating amphetamine-induced hyperlocomotion without affecting basal locomotor activity.[3][10] Conversely, vorinostat was ineffective in these tests.[3] In addition, vorinostat showed dissimilar and lesser effects on gene transcription compared to BRD-6929.[3] These differences may be related to selectivity and duration of exposure, with sustained exposure as with BRD-6929 possibly being advantageous.[3] Aside from its acute effects, BRD-6929 was not well-tolerated and compromised health with chronic administration for 10 days in rodents, whereas no health compromise was observed with chronic administration of vorinostat.[3][8] On the other hand, in another study, BRD-6929 produced longevity-enhancing effects in rodents in multiple organ systems, including the kidney, brain, and heart.[11] BRD-6929 has been found to rescue chlorpyrifos-induced social deficits in zebrafish similarly to butyric acid (butyrate).[12]

Pharmacokinetics

The pharmacokinetics of BRD-6929 in animals have been described.[1][3][4] The drug penetrates into the brain in rodents.[3][4][13] In addition, unlike vorinostat, it showed a sustained duration in the brain in rodents (t1/2 = 0.44 hours and 6.44 hours, respectively).[3] BRD-6929 also penetrates into the brain in baboons, albeit with relatively low brain levels compared to plasma levels.[3]

Chemistry

In terms of chemical structure, BRD-6929 is an ortho-aminoanilide or benzamide and is a close analogue of tacedinaline (CI-994), differing from it only in the addition of a thiophene ring on one of the phenyl rings.[2][4][6]

History

BRD-6929 was first described in the scientific literature in 2005.[1][7][3] Subsequently, it was described in greater detail in 2013 and thereafter.[3][4] The drug's apparent lack of selectivity for HDAC1 and HDAC2 over HDAC3 was first described in 2022.[6]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Recommended Tool Compounds: Isoform- and Class-Specific Histone Deacetylase Inhibitors". ACS Pharmacology & Translational Science 9 (3): 462–489. March 2026. doi:10.1021/acsptsci.5c00619. PMID 41852629. 
  2. ↑ 2.0 2.1 2.2 2.3 "Medicinal chemistry advances in targeting class I histone deacetylases". Exploration of Targeted Anti-Tumor Therapy 4 (4): 757–779. 2023. doi:10.37349/etat.2023.00166. PMID 37711592. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 "A selective HDAC 1/2 inhibitor modulates chromatin and gene expression in brain and alters mouse behavior in two mood-related tests". PLOS ONE 8 (8). 2013. doi:10.1371/journal.pone.0071323. PMID 23967191. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 "FDG-PET imaging reveals local brain glucose utilization is altered by class I histone deacetylase inhibitors". Neuroscience Letters 550: 119–124. August 2013. doi:10.1016/j.neulet.2013.06.016. PMID 23810801. 
  5. ↑ "Oxycodone withdrawal induces HDAC1/HDAC2-dependent transcriptional maladaptations in the reward pathway in a mouse model of peripheral nerve injury". Nature Neuroscience 26 (7): 1229–1244. July 2023. doi:10.1038/s41593-023-01350-3. PMID 37291337. "A recent study using the prototype HDAC1/HDAC2-selective benzamide-derived inhibitor Cpd-60, which potently targets free HDAC3, demonstrated that HDAC3 can associate with CoREST into a catalytically inactive complex following ligand binding45.". 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Resolving the deceptive isoform and complex selectivity of HDAC1/2 inhibitors". Cell Chemical Biology 29 (7): 1140–1152.e5. July 2022. doi:10.1016/j.chembiol.2022.03.002. PMID 35298895. "Here, ortho-aminoanilide-derived HDACis (often also referred to as benzamides), such as CI-994 (tacedinaline, Figure 1A), stand out with high selectivity for HDAC1/2/3. In addition, it was found that 40 -aryl substituted aminoanilides, including the prototype inhibitor Cpd-60 (Figure 1A), displayed apparent high selectivity for HDAC1/2 over the closely related HDAC3 in biochemical HDAC activity assays (Methot et al., 2008). [...] Our data provide strong evidence that Cpd-60 is devoid of HDAC1/2 selectivity over HDAC3. We demonstrate that Cpd-60 has high preference for free over complex-bound HDAC1/2/3 and that the perceived selectivity is based on erroneous conclusions derived from biochemical activity assays, improperly equating results obtained with un-complexed recombinant HDAC1/2 but NCoR-complexed HDAC3. [...] Our findings provide strong evidence that the previously reported selectivity profiles of certain HDACis are artifacts resulting from collective reliance on oversimplified assay designs that ignore both the contributions of complex partners and the relevance of complex dynamics.". 
  7. ↑ 7.0 7.1 "Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2)". Bioorganic & Medicinal Chemistry Letters 18 (3): 973–978. February 2008. doi:10.1016/j.bmcl.2007.12.031. PMID 18182289. 
  8. ↑ 8.0 8.1 "Epigenetic Mechanisms in Psychiatric Diseases and Epigenetic Therapy". Drug Development Research 77 (7): 407–413. November 2016. doi:10.1002/ddr.21340. PMID 27594444. "Schroeder et al. evalauted the effect of novel HDAC inhibitors on specific HDAC subtypes in rodent models of CNS disease. Cpd-60, a benzamine HDAC inhibitor, selective for HDAC1 and HDAC2 produced mood-related behavioral alterations by inducing transcriptional modifications in mouse prefrontal cortex, nucleus accumbens, and hippocampus of genes involved in the regulation of mood-related neurocircuitry that involved a glucocorticoid signaling cascade. However, chronic treatment with Cpd-60 was not well tolerated [Schroeder et al., 2013].". 
  9. ↑ "Dissecting structure-activity-relationships of crebinostat: Brain penetrant HDAC inhibitors for neuroepigenetic regulation". Bioorganic & Medicinal Chemistry Letters 26 (4): 1265–1271. February 2016. doi:10.1016/j.bmcl.2016.01.022. PMID 26804233. "An anti-depressant-like effect has also been shown in preclinical settings in rodent models for several HDAC inhibitors including sodium butyrate [11, 12], SAHA and MS-275 [13], a HDAC1/2-selective inhibitor Cpd-60 [14], and HDAC6-selective inhibitors ACY-738 and ACY-775 [15].". 
  10. ↑ "The Epigenetic Mechanisms of Amphetamine". Journal of Addiction & Prevention 2015 (Suppl 1). 2015. PMID 27453897. "As mentioned above, histone acetylation has been one of the most studied AMPH-induced epigenetic modification [19,22,31,33,34]. However, while some studies have shown HDAC inhibitors potentiate the behavioral effects of AMPH [22,31], others have found they decrease and reverse the AMPH-induced behavioral responses [33,35–38]. For example, Stertz et al. reported that sodium valproate reversed the AMPH-induced locomotor activity and partially reversed the AMPH-induced increase in HDAC activity in nuclear extracts of rat pre-frontal cortex [35]. Moreover, Steckert et al. and Moretti et al. found that in rats, sodium butyrate (SB) completely reverted and prevented the increase of locomotor activity and risk-taking behaviors induced by AMPH [33,36]. These discrepancies can be caused by the use of different animal strains, different brain tissues and different length of AMPH treatment. But, they also could be due to differences in the HDAC isoforms targeted by HDAC inhibitors. In fact, Schroeder et al. demonstrated that in mice the increased locomotor response following acute AMPH treatment was decreased by compound 60 (Cpd-60), an inhibitor of HDAC1 and HDAC2 but not HDAC3 [34]. Moreover, genetic and pharmacological inhibition of HDAC1, but not HDAC2 or HDAC3, produced a significant reduction of cocaine-induced sensitivity [34].". 
  11. ↑ "HDAC1/2 inhibitor therapy improves multiple organ systems in aged mice". iScience 27 (1). January 2024. doi:10.1016/j.isci.2023.108681. PMID 38269100. 
  12. ↑ "Butyrate rescues chlorpyrifos-induced social deficits through inhibition of class I histone deacetylases". bioRxiv. October 2025. doi:10.1101/2025.10.19.683261. PMID 41280077. 
  13. ↑ "PET imaging demonstrates histone deacetylase target engagement and clarifies brain penetrance of known and novel small molecule inhibitors in rat". ACS Chemical Neuroscience 5 (10): 1055–1062. October 2014. doi:10.1021/cn500162j. PMID 25188794. 



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