ML-264 is a novel selective Krüppel-like factor 5 (KLF5) inhibitor. ML-264 inhibits cancer cell proliferation. ML-264 downregulates KLF5/EGR1 expression. ML-264 alters cell cycle to inhibit proliferation. ML-264 is useful for studies on colorectal cancer and KLF5-related tumor mechanisms[1-4].
In vitro, HK-2 cells were treated with 5-20µM ML-264 for 24h. ML-264 aggravated TGF-β-induced apoptosis, aggravated TGF-β-induced fibrosis and G2/M phase cell cycle stalling[5]. Colorectal cancer cell lines and patient-derived colorectal cancer organoids were treated with 10µM ML-264 for 1-7 days. ML-264 decreased Bcl-2 expression, increased Bax expression, ncreased cleaved caspase-3 expression, promoted apoptosis, enhanced oxaliplatin-induced apoptotic response[6]. 143B and U2OS cells were treated with 0.5-2µM ML-264 for 24-96h. ML-264 inhibited cell migration, cell invasion, induced G0/G1 phase cell cycle arrest, inhibited cell proliferation, colony formation[7].
In vivo, nude mice subcutaneously inoculated with DLD-1 cells were intraperitoneally injected with 10-25mg/kg ML-264 twice daily for 10 days. ML-264 inhibited DLD-1 xenograft tumor growth and reduced mitotic figures[8]. BALB/c nude mice were intraperitoneally injected with 10mg/kg ML-264 every 2 days for 32 days. ML-264 inhibited A2780-olaR xenograft tumor growth, decreased Vimentin, KLF4, Ki-67 expression, enhanced Olaparib-induced tumor cell apoptosis[9]. C57BL/6 mice were administered ML-264 every 12h for 28 days starting 12h after permanent left coronary artery ligation. ML-264 improved ejection fraction, reduced ventricular volume, heart weight, early postoperative mortality[10].
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. 2011 Oct 31.
[2] Lu J, Hou Y, Liu SX, et al. Acetyl-CoA synthetase 2 induces pyroptosis and inflammation of renal epithelial tubular cells in sepsis-induced acute kidney injury by upregulating the KLF5/NF-κB pathway. Cell Commun Signal. 2024 Mar 21;22(1):187.
[3] Bhargava D, Rusakow D, Zheng W, et al. KLF5 inhibition initiates epithelial-mesenchymal transition in non-transformed human squamous epithelial cells. Biochim Biophys Acta Mol Cell Res. 2024 Oct;1871(7):119789.
[4] Xie Z, Jie Z, Wang G, et al. TGF-β synergizes with ML264 to block IL-1β-induced matrix degradation mediated by Krüppel-like factor 5 in the nucleus pulposus. Biochim Biophys Acta Mol Basis Dis. 2018 Feb;1864(2):579-589.
[5] Lin L, Shen D, Su Y, et al. Magnesium Lithospermate B protects against ischemic AKI-to-CKD progression via regulating the KLF5/CDK1/Cyclin B1 pathway. Phytomedicine. 2025;142:156765.
[6] Shen X, Zhang Y, Xu Z, et al. KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response. Cell Death Dis. 2022;13:303.
[7] Huang H, Han Y, Chen Z, et al. ML264 inhibits osteosarcoma growth and metastasis via inhibition of JAK2/STAT3 and WNT/β-catenin signalling pathways. J Cell Mol Med. 2020;24(10):5652-5664.
[8] Ruiz de Sabando A, Wang C, He Y, et al. ML264, a novel small-molecule compound that potently inhibits growth of colorectal cancer. Mol Cancer Ther. 2016 Jan;15(1):72-83.
[9] Xiao H, Cheng G, Zhang H, et al. Role of KLF5 in enhancing ovarian cancer stemness and PARPi resistance: mechanisms and therapeutic targeting. J Transl Med. 2025;23:492.
[10] Hoffman M, Palioura D, Kyriazis ID, et al. Cardiomyocyte Krüppel-like factor 5 promotes de novo ceramide biosynthesis and contributes to eccentric remodeling in ischemic cardiomyopathy. Circulation. 2021 Mar 16;143(11):1139-1156.