Indisulam
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MedKoo CAT#: 201540

CAS#: 165668-41-7

Description: Indisulam, also known as E7070, is a carbonic anhydrase inhbitor, is also a novel synthetic sulfonamide that targets the G1 phase of the cell cycle.. The potential antitumor activity of Indisulam was discovered through optimization of the structure-activity relationships of a series of sulfonamide structures. Indisulam causes a blockade in the G1/S transition through inhibition of the activation of both cyclin-dependent kinase 2 and cyclin E. Preclinical studies with Indisulam showed activity in multiple tumor types, most prominently in colon and lung cancer.


Chemical Structure

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Indisulam
CAS# 165668-41-7

Theoretical Analysis

MedKoo Cat#: 201540
Name: Indisulam
CAS#: 165668-41-7
Chemical Formula: C14H12ClN3O4S2
Exact Mass: 384.99577
Molecular Weight: 385.84
Elemental Analysis: C, 43.58; H, 3.13; Cl, 9.19; N, 10.89; O, 16.59; S, 16.62

Price and Availability

Size Price Availability Quantity
10.0mg USD 150.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 750.0 Ready to ship
200.0mg USD 1350.0 Ready to ship
500.0mg USD 2950.0 Ready to ship
1.0g USD 4650.0 Ready to ship
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Synonym: E7070; E 7070; E-7070; ER35744; ER 35744; ER-35744; D04522; Indisulam

IUPAC/Chemical Name: N-(3-Chloro-1H-indol-7-yl)-1,4-benzenedisulfonamide

InChi Key: SETFNECMODOHTO-UHFFFAOYSA-N

InChi Code: InChI=1S/C14H12ClN3O4S2/c15-12-8-17-14-11(12)2-1-3-13(14)18-24(21,22)10-6-4-9(5-7-10)23(16,19)20/h1-8,17-18H,(H2,16,19,20)

SMILES Code: O=S(C1=CC=C(S(=O)(N)=O)C=C1)(NC2=CC=CC3=C2NC=C3Cl)=O

Appearance: White to pink solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO.

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Indisulam (E 7070) is a carbonic anhydrase inhibitor with anticancer activity.
In vitro activity: Similar to this study’s gene expression analysis, indisulam treatment resulted in multiple splicing events that were all dependent on RBM39. Indisulam treatment for 12 h resulted in 1,640 exon-skipping events, 132 intron retention events, and 22 alternative splice site events (Figure 6C). However, no RBM39-independent splicing changes occurred following indisulam treatment in cells expressing the RBM39 G268V allele. In addition, no RBM23-dependent splicing events were detected following auxin treatment in the RBM23-AID cell line (Figure 6C). Taken together, these results suggest that the observed effect of indisulam on splicing is mediated exclusively through RBM39 and not through degradation of RBM23 or any other substrate. Reference: Cell Rep. 2019 Nov 5; 29(6): 1499–1510.e6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950731/
In vivo activity: Finally, this study established VCaP xenografts in castrated male mice to assess the effectiveness of combining indisulam and MDV in vivo relative to the monotherapies. The xenograft study was divided into four arms consisting of vehicle, MDV, indisulam and MDV + indisulam. Dosing for the monotherapies was established from literature precedent. Each arm was dosed on a repeating schedule of five days on then two days off for six weeks (Fig. 6A). Over the course of the study bi-weekly measurements were recorded to track tumor progression. The MDV arm of the study was minimally effective compared to vehicle due to AR-V7-driven growth of the xenografts. As expected, both the indisulam arm and MDV + indisulam arm of the study were significantly effective compared to the MDV arm (Fig. 6A and B). Interestingly, the indisulam arm (152.1 cc ± 20.3 cc at endpoint) was superior to the combination therapy (408.9 cc ± 37.4 cc) and the MDV monotherapy (698.9 cc ± 286.5 cc) (Fig. 6A and B). Reference: Bioorg Med Chem. 2020 Oct 15;28(20):115712. https://pubmed.ncbi.nlm.nih.gov/33069070/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 30.0 77.75

Preparing Stock Solutions

The following data is based on the product molecular weight 385.84 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Melnyk JE, Steri V, Nguyen HG, Hann B, Feng FY, Shokat KM. The splicing modulator sulfonamide indisulam reduces AR-V7 in prostate cancer cells. Bioorg Med Chem. 2020 Oct 15;28(20):115712. doi: 10.1016/j.bmc.2020.115712. Epub 2020 Aug 18. PMID: 33069070. 2. Ting TC, Goralski M, Klein K, Wang B, Kim J, Xie Y, Nijhawan D. Aryl Sulfonamides Degrade RBM39 and RBM23 by Recruitment to CRL4-DCAF15. Cell Rep. 2019 Nov 5;29(6):1499-1510.e6. doi: 10.1016/j.celrep.2019.09.079. PMID: 31693891; PMCID: PMC7950731. 4. Teixeira SA, Viapiano MS, Andrade AF, Nandhu MS, Pezuk JA, Bidinotto LT, Suazo VK, Neder L, Carlotti CG, Becker AP, Tone LG, Scrideli CA. The Carbonic Anhydrase Inhibitor E7070 Sensitizes Glioblastoma Cells to Radio- and Chemotherapy and Reduces Tumor Growth. Mol Neurobiol. 2021 Jun 3. doi: 10.1007/s12035-021-02437-3. Epub ahead of print. PMID: 34085182.
In vitro protocol: 1. Melnyk JE, Steri V, Nguyen HG, Hann B, Feng FY, Shokat KM. The splicing modulator sulfonamide indisulam reduces AR-V7 in prostate cancer cells. Bioorg Med Chem. 2020 Oct 15;28(20):115712. doi: 10.1016/j.bmc.2020.115712. Epub 2020 Aug 18. PMID: 33069070. 2. Ting TC, Goralski M, Klein K, Wang B, Kim J, Xie Y, Nijhawan D. Aryl Sulfonamides Degrade RBM39 and RBM23 by Recruitment to CRL4-DCAF15. Cell Rep. 2019 Nov 5;29(6):1499-1510.e6. doi: 10.1016/j.celrep.2019.09.079. PMID: 31693891; PMCID: PMC7950731.
In vivo protocol: 1. 1. Teixeira SA, Viapiano MS, Andrade AF, Nandhu MS, Pezuk JA, Bidinotto LT, Suazo VK, Neder L, Carlotti CG, Becker AP, Tone LG, Scrideli CA. The Carbonic Anhydrase Inhibitor E7070 Sensitizes Glioblastoma Cells to Radio- and Chemotherapy and Reduces Tumor Growth. Mol Neurobiol. 2021 Jun 3. doi: 10.1007/s12035-021-02437-3. Epub ahead of print. PMID: 34085182. 2. Melnyk JE, Steri V, Nguyen HG, Hann B, Feng FY, Shokat KM. The splicing modulator sulfonamide indisulam reduces AR-V7 in prostate cancer cells. Bioorg Med Chem. 2020 Oct 15;28(20):115712. doi: 10.1016/j.bmc.2020.115712. Epub 2020 Aug 18. PMID: 33069070.

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1. Teixeira SA, Viapiano MS, Andrade AF, Nandhu MS, Pezuk JA, Bidinotto LT, Suazo VK, Neder L, Carlotti CG, Becker AP, Tone LG, Scrideli CA. The Carbonic Anhydrase Inhibitor E7070 Sensitizes Glioblastoma Cells to Radio- and Chemotherapy and Reduces Tumor Growth. Mol Neurobiol. 2021 Jun 3. doi: 10.1007/s12035-021-02437-3. Epub ahead of print. PMID: 34085182. 2. Ting TC, Goralski M, Klein K, Wang B, Kim J, Xie Y, Nijhawan D. Aryl Sulfonamides Degrade RBM39 and RBM23 by Recruitment to CRL4-DCAF15. Cell Rep. 2019 Nov 5;29(6):1499-1510.e6. doi: 10.1016/j.celrep.2019.09.079. PMID: 31693891; PMCID: PMC7950731. 3. Reichermeier KM, Straube R, Reitsma JM, Sweredoski MJ, Rose CM, Moradian A, den Besten W, Hinkle T, Verschueren E, Petzold G, Thomä NH, Wertz IE, Deshaies RJ, Kirkpatrick DS. PIKES Analysis Reveals Response to Degraders and Key Regulatory Mechanisms of the CRL4 Network. Mol Cell. 2020 Mar 5;77(5):1092-1106.e9. doi: 10.1016/j.molcel.2019.12.013. Epub 2020 Jan 20. PMID: 31973889. 4. Han T, Nijhawan D. Exome Sequencing of Drug-Resistant Clones for Target Identification. Methods Mol Biol. 2019;1888:175-187. doi: 10.1007/978-1-4939-8891-4_10. PMID: 30519947. 5. Han T, Goralski M, Gaskill N, Capota E, Kim J, Ting TC, Xie Y, Williams NS, Nijhawan D. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science. 2017 Apr 28;356(6336):eaal3755. doi: 10.1126/science.aal3755. Epub 2017 Mar 16. Erratum in: Science. 2017 May 26;356(6340):null. PMID: 28302793. 6. Pogacar, Ziva & Johnson, Jackie & Krenning, Lenno & De Conti, Giulia & Lieftink, Cor & Velds, Arno & Wardak, Leyma & Jochems, Fleur & Groot, Kelvin & Schepers, Arnout & Wang, Liqin & Song, Ji-Ying & Ven, Marieke & Tellingen, Olaf & Medema, René & Beijersbergen, Roderick & Bernards, Rene & Leite de Oliveira, Rodrigo. (2021). Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity. Cell Reports Medicine, 10.1101/2021.10.18.464788. 7. Singh S, Quarni W, Goralski M, Wan S, Jin H, Van de Velde LA, Fang J, Wu Q, Abu-Zaid A, Wang T, Singh R, Craft D, Fan Y, Confer T, Johnson M, Akers WJ, Wang R, Murray PJ, Thomas PG, Nijhawan D, Davidoff AM, Yang J. Targeting the spliceosome through RBM39 degradation results in exceptional responses in high-risk neuroblastoma models. Sci Adv. 2021 Nov 19;7(47):eabj5405. doi: 10.1126/sciadv.abj5405. Epub 2021 Nov 17. PMID: 34788094; PMCID: PMC8598007. 8.. Jia X, Pan L, Zhu M, Hu H, Zhai L, Liu J, Hu M, Liu B, Tan M. pSILAC method coupled with two complementary digestion approaches reveals PRPF39 as a new E7070-dependent DCAF15 substrate. J Proteomics. 2020 Jan 6;210:103545. doi: 10.1016/j.jprot.2019.103545. Epub 2019 Oct 15. PMID: 31626998.

1: Pogacar Z, Johnson JL, Krenning L, De Conti G, Jochems F, Lieftink C, Velds A, Wardak L, Groot K, Schepers A, Wang L, Song JY, van de Ven M, van Tellingen O, Medema RH, Beijersbergen RL, Bernards R, Leite de Oliveira R. Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity. PLoS One. 2022 Sep 6;17(9):e0273182. doi: 10.1371/journal.pone.0273182. PMID: 36067171; PMCID: PMC9447877.

2: Hopkins MD, Witt RC, Flusche AME, Philo JE, Ozmer GL, Purser GH, Sheaff RJ, Lamar AA. Synthesis and biological evaluation of N-alkyl sulfonamides derived from polycyclic hydrocarbon scaffolds using a nitrogen-centered radical approach. Org Biomol Chem. 2022 Aug 24;20(33):6680-6693. doi: 10.1039/d2ob01291j. PMID: 35950721.

3: Zhou B, Zhou H, Xu L, Cai R, Chen C, Chi B, Tuo X. An insight into the interaction between Indisulam and human serum albumin: Spectroscopic method, computer simulation and in vitro cytotoxicity assay. Bioorg Chem. 2022 Oct;127:106017. doi: 10.1016/j.bioorg.2022.106017. Epub 2022 Jul 9. PMID: 35841666.

4: Pogacar Z, Groot K, Jochems F, Dos Santos Dias M, Mulero-Sánchez A, Morris B, Roosen M, Wardak L, De Conti G, Velds A, Lieftink C, Thijssen B, Beijersbergen RL, Bernards R, Leite de Oliveira R. Genetic and compound screens uncover factors modulating cancer cell response to indisulam. Life Sci Alliance. 2022 May 9;5(9):e202101348. doi: 10.26508/lsa.202101348. PMID: 35534224; PMCID: PMC9095732.

5: Nijhuis A, Sikka A, Yogev O, Herendi L, Balcells C, Ma Y, Poon E, Eckold C, Valbuena GN, Xu Y, Liu Y, da Costa BM, Gruet M, Wickremesinghe C, Benito A, Kramer H, Montoya A, Carling D, Want EJ, Jamin Y, Chesler L, Keun HC. Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high- risk neuroblastoma. Nat Commun. 2022 Mar 16;13(1):1380. doi: 10.1038/s41467-022-28907-3. PMID: 35296644; PMCID: PMC8927615.

6: Yamanaka S, Horiuchi Y, Matsuoka S, Kido K, Nishino K, Maeno M, Shibata N, Kosako H, Sawasaki T. A proximity biotinylation-based approach to identify protein-E3 ligase interactions induced by PROTACs and molecular glues. Nat Commun. 2022 Jan 10;13(1):183. doi: 10.1038/s41467-021-27818-z. PMID: 35013300; PMCID: PMC8748630.

7: Freedy AM, Liau BB. Discovering new biology with drug-resistance alleles. Nat Chem Biol. 2021 Dec;17(12):1219-1229. doi: 10.1038/s41589-021-00865-9. Epub 2021 Nov 19. PMID: 34799733; PMCID: PMC9530778.

8: Singh S, Quarni W, Goralski M, Wan S, Jin H, Van de Velde LA, Fang J, Wu Q, Abu-Zaid A, Wang T, Singh R, Craft D, Fan Y, Confer T, Johnson M, Akers WJ, Wang R, Murray PJ, Thomas PG, Nijhawan D, Davidoff AM, Yang J. Targeting the spliceosome through RBM39 degradation results in exceptional responses in high- risk neuroblastoma models. Sci Adv. 2021 Nov 19;7(47):eabj5405. doi: 10.1126/sciadv.abj5405. Epub 2021 Nov 17. PMID: 34788094; PMCID: PMC8598007.

9: Lu J, Jiang H, Li D, Chen T, Wang Y, Pu Z, Xu G. Proximity Labeling, Quantitative Proteomics, and Biochemical Studies Revealed the Molecular Mechanism for the Inhibitory Effect of Indisulam on the Proliferation of Gastric Cancer Cells. J Proteome Res. 2021 Sep 3;20(9):4462-4474. doi: 10.1021/acs.jproteome.1c00437. Epub 2021 Aug 22. PMID: 34420308.

10: Chen WC, To MD, Westcott PMK, Delrosario R, Kim IJ, Philips M, Tran Q, Bollam SR, Goodarzi H, Bayani N, Mirzoeva O, Balmain A. Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells. Nat Commun. 2021 Jul 13;12(1):4288. doi: 10.1038/s41467-021-24498-7. PMID: 34257283; PMCID: PMC8277813.

11: Lu SX, De Neef E, Thomas JD, Sabio E, Rousseau B, Gigoux M, Knorr DA, Greenbaum B, Elhanati Y, Hogg SJ, Chow A, Ghosh A, Xie A, Zamarin D, Cui D, Erickson C, Singer M, Cho H, Wang E, Lu B, Durham BH, Shah H, Chowell D, Gabel AM, Shen Y, Liu J, Jin J, Rhodes MC, Taylor RE, Molina H, Wolchok JD, Merghoub T, Diaz LA Jr, Abdel-Wahab O, Bradley RK. Pharmacologic modulation of RNA splicing enhances anti-tumor immunity. Cell. 2021 Jul 22;184(15):4032-4047.e31. doi: 10.1016/j.cell.2021.05.038. Epub 2021 Jun 24. PMID: 34171309; PMCID: PMC8684350.

12: Teixeira SA, Viapiano MS, Andrade AF, Nandhu MS, Pezuk JA, Bidinotto LT, Suazo VK, Neder L, Carlotti CG, Becker AP, Tone LG, Scrideli CA. The Carbonic Anhydrase Inhibitor E7070 Sensitizes Glioblastoma Cells to Radio- and Chemotherapy and Reduces Tumor Growth. Mol Neurobiol. 2021 Sep;58(9):4520-4534. doi: 10.1007/s12035-021-02437-3. Epub 2021 Jun 3. PMID: 34085182.

13: Zinn N, Werner T, Doce C, Mathieson T, Boecker C, Sweetman G, Fufezan C, Bantscheff M. Improved Proteomics-Based Drug Mechanism-of-Action Studies Using 16-Plex Isobaric Mass Tags. J Proteome Res. 2021 Mar 5;20(3):1792-1801. doi: 10.1021/acs.jproteome.0c00900. Epub 2021 Feb 23. PMID: 33621079.

14: Xu Y, Nijhuis A, Keun HC. RNA-binding motif protein 39 (RBM39): An emerging cancer target. Br J Pharmacol. 2022 Jun;179(12):2795-2812. doi: 10.1111/bph.15331. Epub 2021 Jan 3. PMID: 33238031.

15: Kim SA, Jo SH, Cho JH, Yu MY, Shin HC, Kim JA, Park SG, Park BC, Kim S, Kim JH. Aryl Sulfonamides Induce Degradation of Aryl Hydrocarbon Receptor Nuclear Translocator through CRL4DCAF15 E3 Ligase. Mol Cells. 2020 Nov 30;43(11):935-944. doi: 10.14348/molcells.2020.0122. PMID: 33168788; PMCID: PMC7700843.

16: Melnyk JE, Steri V, Nguyen HG, Hann B, Feng FY, Shokat KM. The splicing modulator sulfonamide indisulam reduces AR-V7 in prostate cancer cells. Bioorg Med Chem. 2020 Oct 15;28(20):115712. doi: 10.1016/j.bmc.2020.115712. Epub 2020 Aug 18. PMID: 33069070.

17: Hsiehchen D, Goralski M, Kim J, Xie Y, Nijhawan D. Biomarkers for RBM39 degradation in acute myeloid leukemia. Leukemia. 2020 Jul;34(7):1924-1928. doi: 10.1038/s41375-020-0729-9. Epub 2020 Feb 10. PMID: 32042080; PMCID: PMC7819273.

18: Del Prete S, Angeli A, Ghobril C, Hitce J, Clavaud C, Marat X, Supuran CT, Capasso C. Sulfonamide Inhibition Profile of the β-Carbonic Anhydrase from Malassezia restricta, An Opportunistic Pathogen Triggering Scalp Conditions. Metabolites. 2020 Jan 16;10(1):39. doi: 10.3390/metabo10010039. PMID: 31963335; PMCID: PMC7023381.

19: Bussiere DE, Xie L, Srinivas H, Shu W, Burke A, Be C, Zhao J, Godbole A, King D, Karki RG, Hornak V, Xu F, Cobb J, Carte N, Frank AO, Frommlet A, Graff P, Knapp M, Fazal A, Okram B, Jiang S, Michellys PY, Beckwith R, Voshol H, Wiesmann C, Solomon JM, Paulk J. Author Correction: Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex. Nat Chem Biol. 2020 Mar;16(3):361. doi: 10.1038/s41589-020-0471-7. Erratum for: Nat Chem Biol. 2020 Jan;16(1):15-23. PMID: 31942047.

20: Bussiere DE, Xie L, Srinivas H, Shu W, Burke A, Be C, Zhao J, Godbole A, King D, Karki RG, Hornak V, Xu F, Cobb J, Carte N, Frank AO, Frommlet A, Graff P, Knapp M, Fazal A, Okram B, Jiang S, Michellys PY, Beckwith R, Voshol H, Wiesmann C, Solomon JM, Paulk J. Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex. Nat Chem Biol. 2020 Jan;16(1):15-23. doi: 10.1038/s41589-019-0411-6. Epub 2019 Dec 9. Erratum in: Nat Chem Biol. 2020 Mar;16(3):361. PMID: 31819272.



Additional Information

Phase II study of Indisulam: Forty-four patients were randomized. Only minor responses were seen. Myelosuppression, gastrointestinal symptoms, and lethargy were the most common toxicities and were more frequent in the dx1 arm. The pharmacokinetics of indisulam in each treatment schedule were adequately described using a previously developed population pharmacokinetic model and were mostly consistent with the results of the phase I program. Flow cytometric analysis of endobronchial and metastatic disease revealed a reduction in the fraction of cycling cells and an increase in apoptosis following indisulam compared with pretreatment levels. CONCLUSIONS: Despite evidence of tumor-specific indisulam-induced apoptosis, neither of these treatment schedules has single-agent activity as second-line treatment of non-small cell lung cancer. (source: Clin Cancer Res. 2007 Mar 15;13(6):1816-22.)
   
Nano-encapsulated indisulam: This study aimed to begin development of a nanomedicine containing indisulam solubilized in sterically stabilized micelles (SSMs) composed of DSPE-PEG(2000) or sterically stabilized mixed micelles (SSMMs) composed of DSPE-PEG(2000) plus egg phosphatidylcholine. Micelles were prepared by co-precipitation and reconstitution of drug and lipids. Particle size distributions of micellar formulations were determined by quasi-elastic light scattering. Amounts of solubilized drug were determined by reverse-phase high-performance liquid chromatography (RP-HPLC). In vitro cytotoxicity of indisulam in nanocarrier was determined on the MCF-7 cell line by the National Cancer Institute-developed sulforhodamine B assay. Optimal solubilized indisulam concentrations in 5 mM total lipid were 10 microg/mL for SSMMs and 400 microg/mL for SSMs. HPLC results demonstrated that the encapsulation capacity of both micelles was over 95%. In vitro studies showed that indisulam in micellar system was more effective than free indisulam . The optimized formulation was successfully freeze-dried without any addition of lyoprotectants or cryoprotectants. We conclude that SSMs are a promising nanocarrier for indisulam , and indisulam -SSMs should be developed further as a novel targeted nanomedicine. (source: Nanomedicine. 2009 Jun;5(2):178-83.)