Cercosporamide is a ATP-competitive Pkc1 kinase inhibitor (IC50 <50 nM; Ki <7 nM). It also is a unique Mnk inhibitor.

PKC1:50 nM, PKC1:7 nM (ki), MNK:50 nM

Cercosporamide is a broad-spectrum natural antifungal compound and a selective, highly potent fungal Pkc1 kinase inhibitor [1]. Recently, it has been shown to act as a unique Mnk inhibitor with antileukemic properties. Cercosporamide inhibits phosphorylation of eIF4E at Ser209 in AML cells, leading to potent inhibitory effects on primitive leukemic progenitors (CFU-L) from AML patients. Dose-dependent suppression of cell growth is observed in U937 cells and similar results are noted in experiments with MM6 and K562 cells [2].

Treatment with either Cercosporamide or Ara-C alone markedly inhibits xenograft growth compared to their respective controls, achieving statistical significance (P<0.011 for 10 mg/kg Cercosporamide twice-daily; P<0.006 for 20 mg/kg Cercosporamide daily; P<0.0374 for Ara-C). The combined application of Cercosporamide (10 mg/kg twice daily) with Ara-C substantially enhances efficacy beyond that of either compound used singly. Similarly, the synergy of Cercosporamide (20 mg/kg daily) with Ara-C markedly reduces tumor growth compared to both captisol (P<0.0001) and water controls (P=0.0003), albeit without significant superiority over the individual effects of either Cercosporamide (20 mg/kg) or Ara-C alone.