Indisulam
(Synonyms: N-(3-氯-1H-吲哚-7-基)-1,4-苯二磺酰胺,E 7070) 目录号 : GC65549
A sulfonamide with anticancer activity
Cas No.:165668-41-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Indisulam is a sulfonamide with anticancer activity.1 In vitro, indisulam has antiproliferative effects on a wide range of human tumor lines with HCT116 colorectal being the most sensitive and NCI-H596 non-small cell lung cancer (NSCLC) the most resistant (IC50s = 0.11 and 94 μg/ml, respectively). It increases the number of P388 murine leukemia cells in the G1 phase of the cell cycle in a dose-dependent manner and exerts time-dependent cytotoxicity against HCT116 cells. In vivo, indisulam suppresses tumor growth and decreases tumor volume in murine HCT116, SW620, and HCT15 colorectal and LX-1 and PC9 lung cancer xenograft models. Indisulam induces proteasomal degradation of RNA binding motif protein 39 (RBM39) through association with the CUL4-DCAF15 E3 ubiquitin ligase in vitro.2 It is also an inhibitor of carbonic anhydrase in H. pylori (Ki = 310-562 nM).3
1.Ozawa, Y., Sugi, N.H., Nagasu, T., et al.E7070, a novel sulphonamide agent with potent antitumour activity in vitro and in vivoEur. J. Cancer37(17)2275-2282(2001) 2.Han, T., Goralski, M., Gaskill, N., et al.Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15Science356(6336)(2017) 3.Nishimori, I., Vullo, D., Minakuchi, T., et al.Carbonic anhydrase inhibitors: Cloning and sulfonamide inhibition studies of a carboxyterminal truncated α-carbonic anhydrase from Helicobacter pyloriBioorg. Med. Chem. Lett.16(8)2182-2188(2006)
| Cas No. | 165668-41-7 | SDF | Download SDF |
| 别名 | N-(3-氯-1H-吲哚-7-基)-1,4-苯二磺酰胺,E 7070 | ||
| 分子式 | C14H12ClN3O4S2 | 分子量 | 385.85 |
| 溶解度 | DMSO : 100 mg/mL (259.17 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.5917 mL | 12.9584 mL | 25.9168 mL |
| 5 mM | 0.5183 mL | 2.5917 mL | 5.1834 mL |
| 10 mM | 0.2592 mL | 1.2958 mL | 2.5917 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma
Nat Commun 2022 Mar 16;13(1):1380.PMID:35296644DOI:10.1038/s41467-022-28907-3.
Neuroblastoma is the most common paediatric solid tumour and prognosis remains poor for high-risk cases despite the use of multimodal treatment. Analysis of public drug sensitivity data showed neuroblastoma lines to be sensitive to Indisulam, a molecular glue that selectively targets RNA splicing factor RBM39 for proteosomal degradation via DCAF15-E3-ubiquitin ligase. In neuroblastoma models, Indisulam induces rapid loss of RBM39, accumulation of splicing errors and growth inhibition in a DCAF15-dependent manner. Integrative analysis of RNAseq and proteomics data highlight a distinct disruption to cell cycle and metabolism. Metabolic profiling demonstrates metabolome perturbations and mitochondrial dysfunction resulting from Indisulam. Complete tumour regression without relapse was observed in both xenograft and the Th-MYCN transgenic model of neuroblastoma after Indisulam treatment, with RBM39 loss, RNA splicing and metabolic changes confirmed in vivo. Our data show that dual-targeting of metabolism and RNA splicing with anticancer Indisulam is a promising therapeutic approach for high-risk neuroblastoma.
Indisulam Reduces Viability and Regulates Apoptotic Gene Expression in Pediatric High-Grade Glioma Cells
Biomedicines 2022 Dec 27;11(1):68.PMID:36672576DOI:10.3390/biomedicines11010068.
Pediatric high-grade glioma (pHGG) is one of the most aggressive brain tumors. Treatment includes surgery, radiotherapy, chemotherapy, or combination therapy in children older than 3−5 years of age. These devastating tumors are influenced by the hypoxic microenvironment that coordinatively increases the expression of carbonic anhydrases (CA9 and CA12) that are involved in pH regulation, metabolism, cell invasion, and resistance to therapy. The synthetic sulphonamide Indisulam is a potent inhibitor of CAs. The aim of this study was to evaluate the effects of Indisulam on CA9 and CA12 enzymes in pHGG cell lines. Our results indicated that, under hypoxia, the gene and protein expression of CA9 and CA12 are increased in pHGG cells. The functional effects of Indisulam on cell proliferation, clonogenic capacity, and apoptosis were measured in vitro. CA9 and CA12 gene and protein expression were analyzed by RT-PCR and western blot. The treatment with Indisulam significantly reduced cell proliferation (dose-time-dependent) and clonogenic capacity (p < 0.05) and potentiated the effect of apoptosis (p < 0.01). Indisulam promoted an imbalance in the anti-apoptotic BCL2 and pro-apoptotic BAX protein expression. Our results demonstrate that Indisulam contributes to apoptosis via imbalance of apoptotic proteins (BAX/BCL2) and suggests a potential to overcome chemotherapy resistance caused by the regulation these proteins.
Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity
PLoS One 2022 Sep 6;17(9):e0273182.PMID:36067171DOI:10.1371/journal.pone.0273182.
Inducing senescence in cancer cells is emerging as a new therapeutic strategy. In order to find ways to enhance senescence induction by palbociclib, a CDK4/6 inhibitor approved for treatment of metastatic breast cancer, we performed functional genetic screens in palbociclib-resistant cells. Using this approach, we found that loss of CDK2 results in strong senescence induction in palbociclib-treated cells. Treatment with the CDK2 inhibitor Indisulam, which phenocopies genetic CDK2 inactivation, led to sustained senescence induction when combined with palbociclib in various cell lines and lung cancer xenografts. Treating cells with Indisulam led to downregulation of cyclin H, which prevented CDK2 activation. Combined treatment with palbociclib and Indisulam induced a senescence program and sensitized cells to senolytic therapy. Our data indicate that inhibition of CDK2 through Indisulam treatment can enhance senescence induction by CDK4/6 inhibition.
Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15
Science 2017 Apr 28;356(6336):eaal3755.PMID:28302793DOI:10.1126/science.aal3755.
Indisulam is an aryl sulfonamide drug with selective anticancer activity. Its mechanism of action and the basis for its selectivity have so far been unknown. Here we show that Indisulam promotes the recruitment of RBM39 (RNA binding motif protein 39) to the CUL4-DCAF15 E3 ubiquitin ligase, leading to RBM39 polyubiquitination and proteasomal degradation. Mutations in RBM39 that prevent its recruitment to CUL4-DCAF15 increase RBM39 stability and confer resistance to Indisulam's cytotoxicity. RBM39 associates with precursor messenger RNA (pre-mRNA) splicing factors, and inactivation of RBM39 by Indisulam causes aberrant pre-mRNA splicing. Many cancer cell lines derived from hematopoietic and lymphoid lineages are sensitive to Indisulam, and their sensitivity correlates with DCAF15 expression levels. Two other clinically tested sulfonamides, tasisulam and chloroquinoxaline sulfonamide, share the same mechanism of action as Indisulam. We propose that DCAF15 expression may be a useful biomarker to guide clinical trials of this class of drugs, which we refer to as SPLAMs (splicing inhibitor sulfonamides).
Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex
Nat Chem Biol 2020 Jan;16(1):15-23.PMID:31819272DOI:10.1038/s41589-019-0411-6.
The anticancer agent Indisulam inhibits cell proliferation by causing degradation of RBM39, an essential mRNA splicing factor. Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation. To delineate the precise mechanism by which Indisulam mediates the DCAF15-RBM39 interaction, we solved the DCAF15-DDB1-DDA1-indisulam-RBM39(RRM2) complex structure to a resolution of 2.3 Å. DCAF15 has a distinct topology that embraces the RBM39(RRM2) domain largely via non-polar interactions, and Indisulam binds between DCAF15 and RBM39(RRM2), coordinating additional interactions between the two proteins. Studies with RBM39 point mutants and Indisulam analogs validated the structural model and defined the RBM39 α-helical degron motif. The degron is found only in RBM23 and RBM39, and only these proteins were detectably downregulated in indisulam-treated HCT116 cells. This work further explains how Indisulam induces RBM39 degradation and defines the challenge of harnessing DCAF15 to degrade additional targets.