Sm4 is a SOX18 inhibitor (IC₅₀=5.2μM)[1]. Sm4 directly targets the SOX18 HMG domain and preferentially disrupts the interaction between SOX18 and its specific binding partners. Sm4 can be used in research related to tumor metastasis and vascular cancers[2-3].
In vitro, treatment of non-small cell lung cancer cell lines (LXF-289 and SK-MES-1) with Sm4 (10-20μM) for 72 hours induced S-phase cell cycle arrest and upregulated p21 expression[4]. Treatment of human dermal lymphatic endothelial cells (HDLEC) and lymphangiosarcoma cells (MO-LAS) with Sm4 (78-156μM) for 24 hours. Sm4 significantly inhibited the expression of SOX18 at both mRNA and protein levels, while downregulating key lymphatic phenotypic markers (Prox1, Flt4, Lyve1) and impeding cell migration and proliferation[5].
In vivo, nude mice subcutaneously implanted with infantile hemangioma stem cells pretreated with Sm4 (10μM) for 24 hours were orally administered Sm4 (25mg/kg) once daily for 7 days. Sm4 significantly reduced the total vascular density and human CD31-positive vascular density in the implants, without affecting the body weight or blood glucose levels of the mice[6]. NSG mice subcutaneously implanted with a mixture of KSHV-infected lymphatic endothelial progenitor cells (K-ECFCLYs) and KSHV-infected lymphatic endothelial cells (K-LECs) were orally administered Sm4 (25mg/kg) once daily for 10 days. Sm4 significantly decreased the KSHV genome copy numbers within the grafted tissue and reduced the spindle cell morphology[7].
References:
[1] Mathias FRANCOIS. Inhibitors of sox18 protein activity for treating angiogenesis- and/or lymphangiogenesis-related diseases. Patent, WO2018112545A1.
[2] Mei J, Yang K, Zhang X, et al. Intratumoral Collagen Deposition Supports Angiogenesis Suggesting Anti-angiogenic Therapy in Armored and Cold Tumors. Adv Sci (Weinh). 2025 Mar;12(10):e2409147.
[3] Kim I, Koh GY. Taking aim at Sox18. Elife. 2017 Jan 31;6:e24238. doi: 10.7554/eLife.24238.
[4] Rodak O, Mrozowska M, Rusak A, et al. Targeting SOX18 Transcription Factor Activity by Small-Molecule Inhibitor Sm4 in Non-Small Lung Cancer Cell Lines. Int J Mol Sci. 2023 Jul 11;24(14):11316.
[5] Koll KK, Zimmermann MM, Will PA, et al. The Transcription Factor SOX18 Inhibitor Small Molecule 4 Is a Potential Treatment of Cancer-Induced Lymphatic Metastasis and Lymphangiosarcoma. Cancer Rep (Hoboken). 2025 Jan;8(1):e70110.
[6] Seebauer CT, Graus MS, Huang L, et al. Non-beta blocker enantiomers of propranolol and atenolol inhibit vasculogenesis in infantile hemangioma. J Clin Invest. 2022 Feb 1;132(3):e151109.
[7] Tuohinto K, DiMaio TA, Kiss EA, et al. KSHV infection of endothelial precursor cells with lymphatic characteristics as a novel model for translational Kaposi's sarcoma studies. PLoS Pathog. 2023 Jan 23;19(1):e1010753.