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.

LLL12是一种特异性的信号转导和转录激活因子 3 (STAT3)小分子抑制剂，能够抑制STAT3的磷酸化^[1]。STAT3是一种关键的信号转导和转录激活因子，参与细胞周期调控、存活与凋亡、免疫调节、代谢过程以及肿瘤进展等多种生物学功能，其异常激活与多种疾病的发生发展密切相关^[2]。LLL12通过抑制STAT3的活性，能够有效抑制肿瘤细胞的生长、迁移和侵袭，常被用于癌症相关研究^[3-4]。

体外实验中，LLL12对RD2, RH30和 U2OS细胞的IC₅₀值分别为2.85、0.47和1μM，经72小时处理后可显著抑制细胞增殖^[5]。在人肝癌细胞中，LLL12（5或10µM；2小时）能够抑制STAT3信号通路，并阻断白细胞介素-6（IL-6）的抗凋亡活性^[6]。此外，LLL12（在A2780、SKOV3、CAOV-3和OVCAR5细胞中分别使用0.1、1.0、0.1和0.01µM处理72小时）增强了顺铂和紫杉醇对卵巢癌细胞形成、迁移和生长的抑制效果^[4]。

体内实验中，与对照组相比，LLL12（5mg/kg/day；连续13天；腹腔注射）抑制了STAT3的磷酸化，并显著减少了OS-33和SJSA异种移植小鼠的肿瘤体积和肿瘤质量^[7]。