LLL12

LLL12 is a specific small molecule inhibitor of signal transducer and activator of transcription 3 (STAT3) that inhibits STAT3 phosphorylation^[1]. STAT3 is a key signal transducer and transcriptional activator, involved in various biological functions such as cell cycle regulation, survival and apoptosis, immune modulation, metabolic processes, and tumor progression. Its abnormal activation is closely related to the occurrence and development of various diseases^[2]. LLL12 effectively suppresses the growth, migration, and invasion of tumor cells by inhibiting the activity of STAT3 and is commonly used in cancer research^[3-4].

In vitro, the IC₅₀ values of LLL12 for RD2, RH30, and U2OS cells were 2.85μM, 0.47μM, and 1μM, respectively. After 72 hours of treatment, LLL12 significantly inhibited cell proliferation^[5]. LLL12 (5 or 10μM; 2h)inhibits STAT3 signaling and blocks the anti-apoptotic activity of IL-6 in human liver cancer cells^[6]. LLL12 (0.1, 1.0, 0.1 and 0.01µM for A2780, SKOV3, CAOV-3 and OVCAR5, respectively; 72h) enhanced the inhibitory effect of Cisplatin and Paclitaxel on ovarian cancer cell formation, migration, and growth^[4].

In vivo, LLL12 (5mg/kg/day for 13 days; i.p.) suppressed STAT3 phosphorylation and resulted in a significant reduction in tumor volume and tumor mass in the OS-33 and SJSA xenografted mice, relative to the vehicle^[7].

References:
[1] Lin, L., Hutzen, B., Li, P. K., Ball, S., Zuo, M., DeAngelis, S., Foust, E., Sobo, M., Friedman, L., Bhasin, D., Cen, L., Li, C., & Lin, J. (2010). A novel small molecule, LLL12, inhibits STAT3 phosphorylation and activities and exhibits potent growth-suppressive activity in human cancer cells. Neoplasia (New York, N.Y.), 12(1), 39–50.
[2] Ma, J. H., Qin, L., & Li, X. (2020). Role of STAT3 signaling pathway in breast cancer. Cell communication and signaling : CCS, 18(1), 33.
[3] Zuo, M., Li, C., Lin, J., & Javle, M. (2015). LLL12, a novl small inhibitor targeting STAT3 for hepatocellular carcinoma therapy. Oncotarget, 6(13), 10940–10949.
[4] Zhang, R., Chen, X., Fu, S., Xu, L., & Lin, J. (2020). A small molecule STAT3 inhibitor, LLL12, enhances cisplatin and paclitaxelmediated inhibition of cell growth and migration in human ovarian cancer cells. Oncology reports, 44(3), 1224–1232.
[5] Yu, W., Xiao, H., Lin, J., & Li, C. (2013). Discovery of novel STAT3 small molecule inhibitors via in silico site-directed fragment-based drug design. Journal of medicinal chemistry, 56(11), 4402–4412.
[6] Liu, Y., Li, P. K., Li, C., & Lin, J. (2010). Inhibition of STAT3 signaling blocks the anti-apoptotic activity of IL-6 in human liver cancer cells. The Journal of biological chemistry, 285(35), 27429–27439.
[7] Onimoe, G. I., Liu, A., Lin, L., Wei, C. C., Schwartz, E. B., Bhasin, D., Li, C., Fuchs, J. R., Li, P. K., Houghton, P., Termuhlen, A., Gross, T., & Lin, J. (2012). Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice. Investigational new drugs, 30(3), 916–926.