ML264, A Novel Small-Molecule Compound That Potently Inhibits Growth of Colorectal Cancer

Abstract

Colorectal cancer (CRC) is one of the leading causes of cancer mortality in Western civilization. Studies have shown that CRC arises as a consequence of the modification of genes that regulate important cellular functions. Deregulation of the WNT and RAS/MAPK/PI3K signaling pathways has been shown to be important in the early stages of CRC development and progression. Krüppel-like factor 5 (KLF5) is a transcription factor that is highly expressed in the proliferating intestinal crypt epithelial cells. Previously, we showed that KLF5 is a mediator of RAS/MAPK and WNT signaling pathways under homeostatic conditions and that it promotes their tumorigenic functions during the development and progression of intestinal adenomas. Recently, using an ultrahigh-throughput screening (uHTS) approach we identified a number of novel small molecules that have the potential to provide therapeutic benefits for colorectal cancer by targeting KLF5 expression. In the current study, we show that an improved analog of one of these screening hits, ML264, potently inhibits proliferation of CRC cells in vitro through modifications of the cell cycle profile. Moreover, in an established xenograft mouse model of colon cancer, we demonstrate that ML264 efficiently inhibits growth of the tumor within five days of treatment. We show that 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. These findings demonstrate that ML264, or an analog may hold a promise as a novel therapeutic agent to curb the development and progression of colorectal cancer.

Mifepristone Derivative FZU-00,003 Suppresses Triple-negative Breast Cancer Cell Growth partially via miR-153-KLF5 axis

“…Curcumin suppresses bladder cancer cell growth through down-regulating KLF5 expression [29]. ML264, a small molecule inhibitor of KLF5, potently inhibits proliferation of colorectal cancer cells [30]. We recently reported metformin inhibits KLF5 expression and cancer stem cell in basal TNBC [14].…”

Copy number variations of circulating, cell-free DNA in urothelial carcinoma of the bladder patients treated with radical cystectomy: a prospective study

“…Thus, KLF5 could become a promising therapeutic target molecule for UCB. Recently, in an established xenograft mouse model of colon cancer, the drug ML264 efficiently inhibited growth of the tumor within 5 days of treatment by inhibiting the expression of KLF5 and EGR1, a transcriptional activator of KLF5 [ 39 ]. Moreover, in non-muscle invasive UCB treated with TURBT, the tumor suppressive transcription factor ZFHX3 seems to be an independent predictor for disease recurrence [ 22 ].…”

Characterization and phylogenetic analysis of Krüppel-like transcription factor (KLF) gene family in tree shrews (Tupaia belangeri chinensis)

“…KLF5 is an important transcription factor associated with many human cancers, such as breast cancer [64, 65, 72], gastric cancer [73], colorectal cancer [74], bladder cancer [75] and prostate cancer [76]. Post-translational modifications are vital for regulating KLF5 activity.…”