ML264

Description: ML264 is a novel and selective inhibitor of Krüppel-like factor 5 (KLF5) that potently inhibits the proliferation of colorectal cancer cells in vitro through modifications of the cell-cycle profile. Moreover, in an established xenograft mouse model of colon cancer, ML264 efficiently inhibits growth of the tumor within 5 days of treatment. This effect is caused by a significant reduction in proliferation and that ML264 potently inhibits the expression of KLF5 and EGR1, a transcriptional activator of KLF5. ML264 is highly active (IC50 = 29 nM is a cell-based assay for proliferation of DLD-1 cells, IC50 = 81 nM in a cell-based luciferase assay). It lacks cytotoxicity in the IEC-6 control cell line (IC50 > 50 uM, < 50% inhibition was observed at 100 uM). Robust activity was also seen in several other KLF5-expressing cell types as well (e.g., HCT116, IC50 = 560 nM; HT29, IC50 = 130 nM; SW620, IC50 = 430 nM). ML264 does not inhibit kinases associated with the KLF5 pathway, as determined using a panel of 47 selected kinases. Western blot analysis shows that ML264 significantly reduces KLF5 expression. These results demonstrate KLF5 target specificity. An NCI60 panel study using ML264 revealed that it induces death of most colon cancer cell lines, with cytotoxicity toward several other tumor cell lines as well. ML264 is chemically stable, unreactive with glutathione, has suitable aqueous solubility, is highly stable to mouse, rat, and human hepatic microsomes, has favorable properties associated with drug-likeness, and does not inhibit CYP enzymes. Due to these properties in concert with its high cellular potency and selectivity, ML264 is a good candidate for in vivo anticancer studies, with great potential for use in long time-course in situ studies aimed to elucidate the role of KLF5 as a regulator of cellular proliferation and tumor formation in the intestinal epithelium. ML264 and its analogues may hold a promise as a novel therapeutic agent to curb the development and progression of colorectal cancer.

References: Mol Cancer Ther. 2016 Jan; 15(1):72-83; https://www.ncbi.nlm.nih.gov/pubmed/23762940