BRD-6929

BRD-6929
Clinical data
Other namesBRD6929; "Compound 60"; Cpd-60; Cmpd60; Merck60; BRD-692; BRD692
Drug classHistone deacetylase inhibitor; HDAC1, HDAC2, and HDAC3 inhibitor
ATC code
  • None
Identifiers
  • 4-acetamido-N-(2-amino-5-thiophen-2-ylphenyl)benzamide
CAS Number
PubChem CID
ChemSpider
ChEBI
ChEMBL
Chemical and physical data
FormulaC19H17N3O2S
Molar mass351.42 g·mol−1
3D model (JSmol)
  • CC(=O)NC1=CC=C(C=C1)C(=O)NC2=C(C=CC(=C2)C3=CC=CS3)N
  • InChI=1S/C19H17N3O2S/c1-12(23)21-15-7-4-13(5-8-15)19(24)22-17-11-14(6-9-16(17)20)18-3-2-10-25-18/h2-11H,20H2,1H3,(H,21,23)(H,22,24)
  • Key:ABZSPJVXTTUFAA-UHFFFAOYSA-N

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
EnzymeIC50Tooltip Half-maximal inhibitory concentration (nM)
HDAC11
HDAC28–13
HDAC3398–458
HDAC4>33,000
HDAC5>33,000
HDAC6>33,000
HDAC7>33,000
HDAC8>33,000
HDAC9>33,000
HDAC103,400
Refs: [2][3][4][7]

BRD-6929 is a selective inhibitor of HDAC1 and HDAC2, with IC50Tooltip half-maximal inhibitory concentration 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 2 3 4 5 6 Schäker-Hübner L, Hansen FK (March 2026). "Recommended Tool Compounds: Isoform- and Class-Specific Histone Deacetylase Inhibitors". ACS Pharmacology & Translational Science. 9 (3): 462–489. doi:10.1021/acsptsci.5c00619. PMC 12993782. PMID 41852629.
  2. 1 2 3 4 Abdallah DI, de Araujo ED, Patel NH, Hasan LS, Moriggl R, Krämer OH, et al. (2023). "Medicinal chemistry advances in targeting class I histone deacetylases". Exploration of Targeted Anti-Tumor Therapy. 4 (4): 757–779. doi:10.37349/etat.2023.00166. PMC 10497394. PMID 37711592.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Schroeder FA, Lewis MC, Fass DM, Wagner FF, Zhang YL, Hennig KM, et al. (2013). "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) e71323. doi:10.1371/journal.pone.0071323. PMC 3743770. PMID 23967191.
  4. 1 2 3 4 5 6 7 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". Neuroscience Letters. 550: 119–124. doi:10.1016/j.neulet.2013.06.016. PMC 3750730. PMID 23810801.
  5. ↑ Pryce KD, Serafini RA, Ramakrishnan A, Nicolais A, Giosan IM, Polizu C, et al. (July 2023). "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. doi:10.1038/s41593-023-01350-3. PMC 10752505. 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. 1 2 3 4 5 Payne NC, Mazitschek R (July 2022). "Resolving the deceptive isoform and complex selectivity of HDAC1/2 inhibitors". Cell Chemical Biology. 29 (7): 1140–1152.e5. 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. 1 2 Methot JL, Chakravarty PK, Chenard M, Close J, Cruz JC, Dahlberg WK, et al. (February 2008). "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. doi:10.1016/j.bmcl.2007.12.031. PMID 18182289.
  8. 1 2 Karsli-Ceppioglu S (November 2016). "Epigenetic Mechanisms in Psychiatric Diseases and Epigenetic Therapy". Drug Development Research. 77 (7): 407–413. 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. ↑ Ghosh B, Zhao WN, Reis SA, Patnaik D, Fass DM, Tsai LH, et al. (February 2016). "Dissecting structure-activity-relationships of crebinostat: Brain penetrant HDAC inhibitors for neuroepigenetic regulation". Bioorganic & Medicinal Chemistry Letters. 26 (4): 1265–1271. doi:10.1016/j.bmcl.2016.01.022. PMC 4753070. 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. ↑ McCowan TJ, Dhasarathy A, Carvelli L (2015). "The Epigenetic Mechanisms of Amphetamine". Journal of Addiction & Prevention. 2015 (Suppl 1). PMC 4955852. 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. ↑ Tammaro A, Daniels EG, Hu IM, 't Hart KC, Reid K, Juni RP, et al. (January 2024). "HDAC1/2 inhibitor therapy improves multiple organ systems in aged mice". iScience. 27 (1) 108681. doi:10.1016/j.isci.2023.108681. PMC 10805681. PMID 38269100.
  12. ↑ Diaz L, Kong AX, Zhang P, Chi J, Pham K, Johnson M, et al. (October 2025). "Butyrate rescues chlorpyrifos-induced social deficits through inhibition of class I histone deacetylases". bioRxiv. doi:10.1101/2025.10.19.683261. PMC 12633377. PMID 41280077.
  13. ↑ Schroeder FA, Wang C, Van de Bittner GC, Neelamegam R, Takakura WR, Karunakaran A, et al. (October 2014). "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. doi:10.1021/cn500162j. PMC 4198064. PMID 25188794.
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