Indisulam

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.

Indisulam是一种磺胺类抗肿瘤药物和分子胶降解剂，通过与CUL4-DCAF15 E3泛素连接酶结合诱导RNA结合基序蛋白39（RBM39）的蛋白酶体降解，同时抑制碳酸酐酶并阻滞细胞周期在G1期^[1-2]。Indisulam可用于实体瘤、急性髓系白血病和多发性骨髓瘤的相关研究^[3-4]。

在体外，Indisulam（0.5-2μM）预处理细胞30分钟至2小时后，LLS刺激5.5小时。Indisulam能够通过降解RNA结合蛋白RBM39并下调细胞周期蛋白，从而抑制CDK2的激活^[5]。Indisulam（0-10μM）处理人类宫颈癌细胞系（HeLa和C33A）24-72小时，能够诱导RBM39蛋白的降解并导致RNA异常剪接，特别是改变了凋亡调节因子p73的剪接亚型（ΔNp73和TAp73）的比例。Indisulam显著抑制细胞生长、增殖并诱导细胞凋亡^[6]。

在体内，Indisulam（15mg/kg；腹腔注射）处理胆管癌小鼠模型，每周三次，共七次。Indisulam可显著减少肿瘤负荷（表现为肝脏重量/体重比降低）和肿瘤细胞增殖^[7]。Indisulam（12.5mg/kg/day；共7天）用于处理经尾静脉注射携带荧光素酶的CMK细胞构建的急性髓白血病小鼠模型。Indisulam显著降低了脾脏、肝脏、骨骼（股骨和胫骨）的白血病负荷，并减少了骨髓、脾脏和肝脏组织中Ki67阳性细胞和CD45+白血病细胞的比例^[8]。