Romidepsin

Romidepsin, also known as FK228, is a natural bicyclic depsipeptide that, following reduction, selectively inhibits class I histone deacetylases (HDACs).¹ Reduction of a disulfide bond on romidepsin within the cell generates a zinc-binding thiol, allowing potent and selective inhibition of HDAC1, 2, 3, and 8 (IC₅₀s = 53, 39, 53, and 26 nM, respectively) over HDAC4, 6, 7, and 9 (IC₅₀s = 470, 330, 3,200, and 12,000 nM, respectively).^2,3 Through its effects on HDACs, romidepsin has anti-cancer activities, particularly against certain T cell lymphomas.^4,5,6 Romidepsin also increases mRNA expression and nuclear protein levels of HDAC2, H3 acetylation and transcription of Grin2a, the gene for the NMDA receptor NR2A subunit, and protein levels of the NR2A subunit in the brain of Shank3-deficient mice, a model of autism.⁷ It also increases excitatory postsynaptic currents (EPSCs) in prefrontal cortex pyramidal neurons from Shank3-deficient mice. In addition, romidepsin rescues autism-like social deficits in Shank3-deficient mice for at least three weeks following administration of a 0.25 mg/kg per day dose for three days.

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1. Nakajima, H., Kim, Y.B., Terano, H., et al. FR901228, a potent antitumor antibiotic, is a novel histone descetylase inhibitor. Exp. Cell Res. 241(1), 126-133 (1998).

2. Wang, C., Henkes, L.M., Doughty, L.B., et al. Thailandepsins: Bacterial products with potent histone deacetylase inhibitory activities and broad-spectrum antiproliferative activities. J. Nat. Prod. 74(10), 2031-2038 (2011).

3. Mazitschek, R., Patel, V., Wirth, D.F., et al. Development of a fluorescence polarization based assay for histone deacetylase ligand discovery. Bioorg. Med. Chem. Lett. 18(9), 2809-2812 (2008).

4. Ueda, H., Manda, T., Matsumoto, S., et al. FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. III. Antitumor activities on experimental tumors in mice. J. Antibiot. (Tokyo) 47(3), 315-323 (1994).

5. VanderMolen, K.M., McCulloch, W., Pearce, C.J., et al. Romidepsin (Istodaxr, NSC 630176, FR901228, FK228, depsipeptide): A natural product recently approved for cutaneous T-cell lymphoma. J. Antibiot. (Tokyo) 67(8), 525-231 (2015).

6. Coiffier, B., Federico, M., Caballero, D., et al. Therapeutic options in relapsed or refractory peripheral T-cell lymphoma. Cancer Treat. Rev. 40(9), 1080-1088 (2014).

7. Qin, L., Ma, K., Wang, Z.-J., et al. Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition. Nat. Neurosci. 21(4), 564-575 (2018).