Pimelic Diphenylamide 106

Pimelic diphenylamide 106 is a slow, tight-binding inhibitor of class I histone deacetylases (HDACs).¹ Unlike the HDAC inhibitor suberoylanilide hydroamic acid, which has a fast-on/fast-off HDAC binding rate, pimelic diphenylamide 106 progressively binds HDACs and remains bound after wash-out. As a result, the IC₅₀ of pimelic diphenylamide 106 decreases over time. With prolonged preincubation (1-3 hours), pimelic diphenylamide inhibits the class I HDACs (IC₅₀ = 150, 760, 370, and 5,000 nM for HDAC1, 2, 3, and 8, respectively) but not the class II HDACs (IC₅₀ > 180 μM for HDAC4, 5, and 7).¹ Pimelic diphenylamide 106 and related benzamide HDAC inhibitors may have therapeutic value in Friedrich’s ataxia^1,2,3 and Huntington’s disease,⁴ in part due to their low animal toxicity.

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1. Chou, C.J., Herman, D., and Gottesfeld, J.M. Pimelic diphenylamide 106 is a slow, tight-binding inhibitor of class I histone deacetylases. The Journal of Biological Chemisty 283(51), 35402-35409 (2008).

2. Rai, M., Soragni, E., Jenssen, K., et al. HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model. PLoS One 3(4), (2008).

3. Herman, D., Jenssen, K., Burnett, R., et al. Histone deacetylase inhibitors reverse gene silencing in Friedreich’s ataxia. Nat. Chem. Biol. 2(10), 551-558 (2006).

4. Thomas, E.A., Coppola, G., Desplats, P.A., et al. The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington’s disease transgenic mice. Proc. Natl. Acad. Sci. USA 105(40), 15564-15569 (2008).