FLLL32 (Synonyms: JAK2 Inhibitor X)

FLLL32 is a small molecule analog of curcumin. It can inhibit signal transducer and activator of transcription-3 (STAT3). In the pSTAT3-positive A375 cell line, FLLL32 resulted in pro-apoptotic effects with an IC50 value of 1.3 μM at 48 hours [1].

Activation of STAT3 in melanoma tumors is related to poor prognosis. STAT3 can promote angiogenesis and cell proliferation, drive invasion and metastasis, and inhibit apoptosis [1].

In multiple human melanoma cell lines, after a 24 hour treatment with FLLL32, the STAT3 phosphorylation at Tyr705 but not at Tyr727 was inhibited. In a prior in vitro cell-free assay, FLLL32 was found to inhibit the activity of Jak2 kinase. But in the experiment with multiple human melanoma cell line, no appreciable alteration in the phosphorylation of Jak2, even when the concentration of FLLL32 was 8 μM, was observed. This meant that FLLL32 likely directly acted against the STAT3 protein. FLLL32 at concentrations ranged from 2-4 μM for only 4 hours reduced pSTAT3 and induce cell death [1].

In an s.c. model of B16F10 melanoma in C57BL/6 mice, compared to the treatment with DMSO to the same animals, daily i.p. administration of FLLL-32 at concentrations of 25 mg/kg and 50 mg/kg significantly delayed tumor growth (p<0.001) [2].

References:
[1].  Bill MA, Fuchs JR, Li C, et al. The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity. Molecular cancer, 2010, 9(1): 165.
[2].  Lesinski G, Bill M, Li C, et al. Abstract# 856: The small molecule curcumin analog FLLL-32 induces apoptosis in human melanoma cells via STAT3 inhibition and elicits in vivo anti-tumor activity. Cancer Research, 2009, 69(9 Supplement): 856-856.