RK-33 | DDX3 inhibitor | CAS#1070773-09-9

MedKoo Cat#: 406835 | Name: RK-33

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Description:

WARNING: This product is for research use only, not for human or veterinary use.

RK-33 is a potent and selective DDX3 inhibitor. RK-33 binds to DDX3 and abrogates its activity. Inhibition of DDX3 by RK-33 caused G1 cell cycle arrest, induced apoptosis, and promoted radiation sensitization in DDX3-overexpressing cells. Overall, inhibition of DDX3 by RK-33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for lung cancer therapy. RK-33 radiosensitizes prostate cancer cells by blocking the RNA helicase DDX3.

Chemical Structure

RK-33

CAS#1070773-09-9

Theoretical Analysis

MedKoo Cat#: 406835

Name: RK-33

CAS#: 1070773-09-9

Chemical Formula: C23H20N6O3

Exact Mass: 428.1597

Molecular Weight: 428.45

Elemental Analysis: C, 64.48; H, 4.71; N, 19.62; O, 11.20

Price and Availability

Size	Price	Availability	Quantity
1g	USD 3,450.00
2g	USD 6,250.00
5g	USD 12,950.00

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Related CAS #

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Synonym

RK-33; RK 33; RK33.

IUPAC/Chemical Name

3,7-dihydro-3,7-bis[(4-methoxyphenyl)methyl]-2H-diimidazo[4,5-d:4',5'-f][1,3]diazepin-2-one

InChi Key

COUMZXFUZDBRCZ-UHFFFAOYSA-N

InChi Code

InChI=1S/C23H20N6O3/c1-31-17-7-3-15(4-8-17)11-28-14-26-19-20-22(25-13-24-21(19)28)29(23(30)27-20)12-16-5-9-18(32-2)10-6-16/h3-10,13-14H,11-12H2,1-2H3

SMILES Code

O=C1N(CC2=CC=C(OC)C=C2)C3=NC=NC4=C(N=CN4CC5=CC=C(OC)C=C5)C3=N1

Appearance

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

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

More Info

Product Data

Product Data

Instruction

View handling instruction

Biological target:

RK-33 is an inhibitor of DDX3 and causes G1 cell cycle arrest, induces apoptosis, and promotes radiation sensitization in DDX3-overexpressing cells.

In vitro activity:

This study supports the use of RK-33 as a host-targeted antiviral strategy to control SARS-CoV-2 infection. Targeting DDX3 with RK-33 reduced the viral load in four isolates of SARS-CoV-2 by one to three log orders in Calu-3 cells. Proteomics and RNA-seq analyses indicated that most SARS-CoV-2 genes were downregulated by RK-33 treatment. Reference: Front Microbiol. 2022 Aug 25;13:959577. https://pubmed.ncbi.nlm.nih.gov/36090095/

In vivo activity:

RK-33 inhibits DDX3 activity and down-regulates WNT/β-catenin signaling. It could be used as a therapeutic strategy for DDX3-expressing medulloblastomas in combination with radiation.The combination of RK-33 and 5 Gy radiation caused tumor regression in a mouse xenograft model of medulloblastoma. The researchers observed DDX3 expression in both pediatric (55%) and adult (66%) medulloblastoma patients. Reference: Transl Oncol. 2019 Jan;12(1):96-105. https://pubmed.ncbi.nlm.nih.gov/30292066/

	Solvent	mg/mL	mM
Solubility
	DMSO	40.0	93.36

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 428.45 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.

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. Vesuna F, Akhrymuk I, Smith A, Winnard PT Jr, Lin SC, Panny L, Scharpf R, Kehn-Hall K, Raman V. RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2. Front Microbiol. 2022 Aug 25;13:959577. doi: 10.3389/fmicb.2022.959577. PMID: 36090095; PMCID: PMC9453862. 2. Xie M, Vesuna F, Tantravedi S, Bol GM, Heerma van Voss MR, Nugent K, Malek R, Gabrielson K, van Diest PJ, Tran PT, Raman V. RK-33 Radiosensitizes Prostate Cancer Cells by Blocking the RNA Helicase DDX3. Cancer Res. 2016 Nov 1;76(21):6340-6350. doi: 10.1158/0008-5472.CAN-16-0440. Epub 2016 Sep 12. PMID: 27634756; PMCID: PMC5576499. 3. Tantravedi S, Vesuna F, Winnard PT Jr, Martin A, Lim M, Eberhart CG, Berlinicke C, Raabe E, van Diest PJ, Raman V. Targeting DDX3 in Medulloblastoma Using the Small Molecule Inhibitor RK-33. Transl Oncol. 2019 Jan;12(1):96-105. doi: 10.1016/j.tranon.2018.09.002. Epub 2018 Oct 3. PMID: 30292066; PMCID: PMC6171097. 4. Chen W, Pilling D, Gomer RH. The mRNA-binding protein DDX3 mediates TGF-β1 upregulation of translation and promotes pulmonary fibrosis. JCI Insight. 2023 Apr 10;8(7):e167566. doi: 10.1172/jci.insight.167566. PMID: 36821384; PMCID: PMC10132153.

In vitro protocol:

In vivo protocol:

1. Tantravedi S, Vesuna F, Winnard PT Jr, Martin A, Lim M, Eberhart CG, Berlinicke C, Raabe E, van Diest PJ, Raman V. Targeting DDX3 in Medulloblastoma Using the Small Molecule Inhibitor RK-33. Transl Oncol. 2019 Jan;12(1):96-105. doi: 10.1016/j.tranon.2018.09.002. Epub 2018 Oct 3. PMID: 30292066; PMCID: PMC6171097. 2. Chen W, Pilling D, Gomer RH. The mRNA-binding protein DDX3 mediates TGF-β1 upregulation of translation and promotes pulmonary fibrosis. JCI Insight. 2023 Apr 10;8(7):e167566. doi: 10.1172/jci.insight.167566. PMID: 36821384; PMCID: PMC10132153.

1: Vesuna F, Akhrymuk I, Smith A, Winnard PT Jr, Lin SC, Panny L, Scharpf R, Kehn-Hall K, Raman V. RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2. Front Microbiol. 2022 Aug 25;13:959577. doi: 10.3389/fmicb.2022.959577. PMID: 36090095; PMCID: PMC9453862. 2: Vesuna F, Akhrymuk I, Smith A, Winnard PT, Lin SC, Scharpf R, Kehn-Hall K, Raman V. RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2. bioRxiv [Preprint]. 2022 Mar 1:2022.02.28.482334. doi: 10.1101/2022.02.28.482334. Update in: Front Microbiol. 2022 Aug 25;13:959577. doi: 10.3389/fmicb.2022.959577. PMID: 35262079; PMCID: PMC8902879. 3: Yang SNY, Atkinson SC, Audsley MD, Heaton SM, Jans DA, Borg NA. RK-33 Is a Broad-Spectrum Antiviral Agent That Targets DEAD-Box RNA Helicase DDX3X. Cells. 2020 Jan 9;9(1):170. doi: 10.3390/cells9010170. PMID: 31936642; PMCID: PMC7016805. 4: Xie M, Vesuna F, Tantravedi S, Bol GM, Heerma van Voss MR, Nugent K, Malek R, Gabrielson K, van Diest PJ, Tran PT, Raman V. RK-33 Radiosensitizes Prostate Cancer Cells by Blocking the RNA Helicase DDX3. Cancer Res. 2016 Nov 1;76(21):6340-6350. doi: 10.1158/0008-5472.CAN-16-0440. Epub 2016 Sep 12. PMID: 27634756; PMCID: PMC5576499. 5: Bol GM, Khan R, Heerma van Voss MR, Tantravedi S, Korz D, Kato Y, Raman V. PLGA nanoparticle formulation of RK-33: an RNA helicase inhibitor against DDX3. Cancer Chemother Pharmacol. 2015 Oct;76(4):821-7. doi: 10.1007/s00280-015-2851-3. Epub 2015 Sep 2. PMID: 26330329; PMCID: PMC4878412. 6: Tantravedi S, Vesuna F, Winnard PT Jr, Martin A, Lim M, Eberhart CG, Berlinicke C, Raabe E, van Diest PJ, Raman V. Targeting DDX3 in Medulloblastoma Using the Small Molecule Inhibitor RK-33. Transl Oncol. 2019 Jan;12(1):96-105. doi: 10.1016/j.tranon.2018.09.002. Epub 2018 Oct 3. PMID: 30292066; PMCID: PMC6171097. 7: Heerma van Voss MR, van Diest PJ, Raman V. Targeting RNA helicases in cancer: The translation trap. Biochim Biophys Acta Rev Cancer. 2017 Dec;1868(2):510-520. doi: 10.1016/j.bbcan.2017.09.006. Epub 2017 Sep 28. PMID: 28965870; PMCID: PMC5675762. 8: Mao Q, Ma S, Li S, Zhang Y, Li S, Wang W, Wang F, Guo Z, Wang C. PRRSV hijacks DDX3X protein and induces ferroptosis to facilitate viral replication. Vet Res. 2024 Aug 18;55(1):103. doi: 10.1186/s13567-024-01358-y. PMID: 39155369; PMCID: PMC11331664. 9: Karmakar S, Rauth S, Nallasamy P, Perumal N, Nimmakayala RK, Leon F, Gupta R, Barkeer S, Venkata RC, Raman V, Rachagani S, Ponnusamy MP, Batra SK. RNA Polymerase II-Associated Factor 1 Regulates Stem Cell Features of Pancreatic Cancer Cells, Independently of the PAF1 Complex, via Interactions With PHF5A and DDX3. Gastroenterology. 2020 Nov;159(5):1898-1915.e6. doi: 10.1053/j.gastro.2020.07.053. Epub 2020 Aug 8. PMID: 32781084; PMCID: PMC7680365. 10: Wilky BA, Kim C, McCarty G, Montgomery EA, Kammers K, DeVine LR, Cole RN, Raman V, Loeb DM. RNA helicase DDX3: a novel therapeutic target in Ewing sarcoma. Oncogene. 2016 May 19;35(20):2574-83. doi: 10.1038/onc.2015.336. Epub 2015 Sep 14. PMID: 26364611. 11: Liu Y, Zhang Y, Wang C, Liu Q, Li T, Wang W, Yang F, Li Z, Bai X, Wang Y. Inhibition of DDX3X alleviates persistent inflammation, immune suppression and catabolism syndrome in a septic mice model. Int Immunopharmacol. 2023 Apr;117:109779. doi: 10.1016/j.intimp.2023.109779. Epub 2023 Feb 18. PMID: 36806038. 12: Heerma van Voss MR, Vesuna F, Bol GM, Afzal J, Tantravedi S, Bergman Y, Kammers K, Lehar M, Malek R, Ballew M, Ter Hoeve N, Abou D, Thorek D, Berlinicke C, Yazdankhah M, Sinha D, Le A, Abrahams R, Tran PT, van Diest PJ, Raman V. Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment. Oncogene. 2018 Jan 4;37(1):63-74. doi: 10.1038/onc.2017.308. Epub 2017 Sep 4. PMID: 28869602; PMCID: PMC5756132. 13: Randolph ME, Afifi M, Gorthi A, Weil R, Wilky BA, Weinreb J, Ciero P, Ter Hoeve N, van Diest PJ, Raman V, Bishop AJR, Loeb DM. RNA Helicase DDX3 Regulates RAD51 Localization and DNA Damage Repair in Ewing Sarcoma. bioRxiv [Preprint]. 2023 Jun 10:2023.06.10.544474. doi: 10.1101/2023.06.10.544474. Update in: iScience. 2024 Jan 16;27(2):108925. doi: 10.1016/j.isci.2024.108925. PMID: 37333164; PMCID: PMC10274875. 14: Feng D, Li J, Guo L, Liu J, Wang S, Ma X, Song Y, Liu J, Hao E. DDX3X alleviates doxorubicin-induced cardiotoxicity by regulating Wnt/β-catenin signaling pathway in an in vitro model. J Biochem Mol Toxicol. 2022 Aug;36(8):e23077. doi: 10.1002/jbt.23077. Epub 2022 Apr 25. PMID: 35467791; PMCID: PMC9539463. 15: Liu Y, Zhang Y, Liu Q, Li T, Wang W, Li H, Yang F, Gao W, Li Z, Bai X, Wang Y. Inhibition of DDX3X ameliorated CD4+ T cells pyroptosis and improves survival in septic mice. Mol Immunol. 2023 Feb;154:54-60. doi: 10.1016/j.molimm.2022.12.014. Epub 2023 Jan 3. PMID: 36603305. 16: Bol GM, Vesuna F, Xie M, Zeng J, Aziz K, Gandhi N, Levine A, Irving A, Korz D, Tantravedi S, Heerma van Voss MR, Gabrielson K, Bordt EA, Polster BM, Cope L, van der Groep P, Kondaskar A, Rudek MA, Hosmane RS, van der Wall E, van Diest PJ, Tran PT, Raman V. Targeting DDX3 with a small molecule inhibitor for lung cancer therapy. EMBO Mol Med. 2015 May;7(5):648-69. doi: 10.15252/emmm.201404368. PMID: 25820276; PMCID: PMC4492822. 17: Tantravedi S, Vesuna F, Winnard PT Jr, Van Voss MRH, Van Diest PJ, Raman V. Role of DDX3 in the pathogenesis of inflammatory bowel disease. Oncotarget. 2017 Dec 15;8(70):115280-115289. doi: 10.18632/oncotarget.23323. PMID: 29383159; PMCID: PMC5777771. 18: Cui BC, Sikirzhytski V, Aksenova M, Lucius MD, Levon GH, Mack ZT, Pollack C, Odhiambo D, Broude E, Lizarraga SB, Wyatt MD, Shtutman M. Pharmacological inhibition of DEAD-Box RNA Helicase 3 attenuates stress granule assembly. Biochem Pharmacol. 2020 Dec;182:114280. doi: 10.1016/j.bcp.2020.114280. Epub 2020 Oct 10. PMID: 33049245; PMCID: PMC7686075. 19: Heerma van Voss MR, Kammers K, Vesuna F, Brilliant J, Bergman Y, Tantravedi S, Wu X, Cole RN, Holland A, van Diest PJ, Raman V. Global Effects of DDX3 Inhibition on Cell Cycle Regulation Identified by a Combined Phosphoproteomics and Single Cell Tracking Approach. Transl Oncol. 2018 Jun;11(3):755-763. doi: 10.1016/j.tranon.2018.04.001. Epub 2018 Apr 24. PMID: 29684792; PMCID: PMC6050443. 20: Winnard PT Jr, Vesuna F, Bol GM, Gabrielson KL, Chenevix-Trench G, Ter Hoeve ND, van Diest PJ, Raman V. Targeting RNA helicase DDX3X with a small molecule inhibitor for breast cancer bone metastasis treatment. Cancer Lett. 2024 Sep 19;604:217260. doi: 10.1016/j.canlet.2024.217260. Epub ahead of print. PMID: 39306228.