Indisulam is a sulfonamide anticancer agent and molecular glue degrader. Indisulam binds to the CUL4-DCAF15 E3 ubiquitin ligase complex, thereby inducing proteasomal degradation of the RNA-binding motif protein 39 (RBM39). Indisulam also inhibits carbonic anhydrase and arrests the cell cycle in the G1 phase[1-2]. Indisulam is used in research related to solid tumors, acute myeloid leukemia, and multiple myeloma[3-4].
In vitro, cells were pretreated with Indisulam (0.5-2μM) for 30 minutes to 2 hours, followed by LLS stimulation for 5.5 hours. Indisulam induced the degradation of the RNA-binding protein RBM39 and downregulated cyclin H, thereby inhibiting CDK2 activation[5]. Human cervical cancer cell lines (HeLa and C33A) were treated with Indisulam (0-10μM) for 24-72 hours. Indisulam induced RBM39 degradation and caused aberrant RNA splicing, specifically altering the ratio of apoptotic regulator p73 splice isoforms (ΔNp73 and TAp73). Indisulam significantly inhibited cell growth and proliferation and induced apoptosis[6].
In vivo, a cholangiocarcinoma mouse model was treated with Indisulam (15mg/kg; intraperitoneal injection) three times a week for a total of seven doses. Indisulam significantly reduced tumor burden (as evidenced by a decreased liver weight/body weight ratio) and tumor cell proliferation[7]. In an acute megakaryoblastic leukemia (AMKL) mouse model established by tail vein injection of luciferase-expressing CMK cells, the mice were treated with Indisulam (25mg/kg/day) for 7 days. Indisulam significantly reduced the leukemic burden in the spleen, liver, and bones (femur and tibia), and decreased the proportions of Ki67-positive cells and CD45+ leukemia cells in the bone marrow, spleen, and liver tissues[8].
References:
[1] Ozawa Y, Sugi NH, Nagasu T, et al. E7070, a novel sulphonamide agent with potent antitumour activity in vitro and in vivo. Eur J Cancer. 2001 Nov;37(17):2275-82.
[2] Abbate F, Casini A, Owa T, et al. Carbonic anhydrase inhibitors: E7070, a sulfonamide anticancer agent, potently inhibits cytosolic isozymes I and II, and transmembrane, tumor-associated isozyme IX. Bioorg Med Chem Lett. 2004 Jan 5;14(1):217-23.
[3] Lu SX, De Neef E, Thomas JD, et al. Pharmacologic modulation of RNA splicing enhances anti-tumor immunity. Cell. 2021 Jul 22;184(15):4032-4047.e31.
[4] Han T, Goralski M, Gaskill N, et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science. 2017 Apr 28;356(6336):eaal3755.
[5] Pogacar Z, Johnson JL, Krenning L, et al. Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity. PLoS One. 2022 Sep 6;17(9):e0273182.
[6] Dou Z, Zhang X, Su W, et al. Indisulam exerts anticancer effects via modulation of transcription, translation and alternative splicing on human cervical cancer cells. Am J Cancer Res. 2023 Jul 15;13(7):2922-2937.
[7] Liu N, Zhang J, Chen W, et al. RBM39 Enhances Cholangiocarcinoma Growth Through EZH2-mediated WNT7B/β-catenin Pathway. Cell Mol Gastroenterol Hepatol. 2025;19(1):101404.
[8] Yang Y, Li Z, Yang Y, et al. The RBM39 degrader indisulam inhibits acute megakaryoblastic leukemia by altering the alternative splicing of ZMYND8. Cell Biosci. 2025 Apr 13;15(1):46. doi: 10.1186/s13578-025-01380-3.