Simple modifications to the anhydride moiety of norcantharidin have lead to the development of a series of analogues displaying modest PP1 inhibition (low μM IC₅₀s) comparable to that of norcantharidin (PP1 IC₅₀ = 10.3 ± 1.37 μM). However, unlike norcantharidin, which is a potent inhibitor of PP2A (IC₅₀ = 2.69 ± 1.37 μM), these analogues show reduced PP2A inhibitory action resulting in the development of selective PP1 inhibitory compounds. Data indicates that the introduction of two ortho-disposed substituents on an aromatic ring, or para-substituent favours PP1 inhibition over PP2A inhibition. Introduction of a p-morphilinoaniline substituent, 35, affords an inhibitor displaying PP1 IC₅₀ = 6.5 ± 2.3 μM; and PP2A IC₅₀ = 7.9 ± 0.82 μM (PP1/PP2A = 0.82); and a 2,4,6-trimethylaniline, 23, displaying PP1 IC₅₀ = 48 ± 9; and PP2A IC₅ 85 ± 3 μM (PP1/PP2A = 0.56). The latter shows a 7-fold improvement in PP1 versus PP2A selectivity when compared with norcantharidin. Subsequent analysis of 23 and 35 as potential PP2B inhibitors revealed modest inhibition with IC₅₀s of 89 ± 6 and 42 ± 3 μM, respectively, and returned with PP1/PP2B selectivities of 0.54 and 0.15. Thus, these analogues are the simplest and most selective PP1 inhibitors retaining potency reported to date.
Bioorganic and Medicinal Chemistry Vol. 15, Issue 23, p. 7301-7310