ML264, a potent and selective inhibitor of kruppel-like factor 5 (KLF5), inhibits the growth of colorectal cancer. ML264 is chemically stable, unreactive with glutathione, has suitable aqueous solubility, is highly stable to mouse, rat, and human hepatic microsomes, making it a good candidate for in vivo anticancer studies [1].

ML264 inhibits the MAPK pathway by reducing EGR1 and KLF5 levels. KLF5 is a zinc finger-containing transcription factor which is highly expressed in rapidly dividing intestinal epithelial cells. KLF5 binds to GC-rich sequences in promoters of numerous genes, such as cyclin D1, cyclin B1/Cdc2, and integrin-linked kinase. KLF5 mediates the transforming effects of oncogenic H-Ras and plays an important role in regulating colon cancer pathogenesis [1].

In vitro: In a cell-based assay for proliferation of DLD-1 cells, the IC50 of ML264 was 29 nM. In a cell-based luciferase assay, the IC50 of ML264 was 81 nM. ML264 showed no cytotoxicity in the IEC-6 control cell line with an IC50 of >50 μM. The IC50 of ML264 was 560 nM, 130 nM and 130 nM in HCT116, HT29 and SW620, respectively. ML264 significantly reduced KLF5 expression. ML264 didn’t inhibit kinases associated with the KLF5 pathway. ML264 induced death of most colon cancer cell lines, with cytotoxicity toward several other tumor cell lines as well [1].

In vivo: In an established xenograft mouse model of colon cancer, ML264 efficiently inhibited growth of the tumor within five days treatment. This effect was caused by a significant reduction in proliferation and that ML264 potently inhibited the expression of KLF5 and EGR1, a transcriptional activator of KLF5 and EGR1, a transcriptional activator of KLF5 [2].

References:
[1].  Bialkowska A, Crisp M, Madoux F, et al. ML264: An Antitumor Agent that Potently and Selectively Inhibits Krüppel-like Factor Five (KLF5) Expression: A Probe for Studying Colon Cancer Development and Progression[J]. 2013.
[2].  de Sabando A R, Wang C, He Y, et al. ML264, A Novel Small-Molecule Compound That Potently Inhibits Growth of Colorectal Cancer[J]. Molecular cancer therapeutics, 2016, 15(1): 72-83.