WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H205891
CAS#: 66592-89-0 (HCl)
Description: Kevetrin ( thioureidobutyronitrile), is a water-soluble, small molecule and activator of the tumor suppressor protein p53, with potential antineoplastic activity. Upon intravenous administration, thioureidobutyronitrile activates p53 which in turn induces the expressions of p21 and PUMA (p53 up-regulated modulator of apoptosis), thereby inhibiting cancer cell growth and causing tumor cell apoptosis. Thioureidobutyronitrile may be effective in drug-resistant cancers with mutated p53. p53 tumor suppressor, a transcription factor regulating the expression of many stress response genes and mediating various anti-proliferative processes, is often mutated in cancer cells.
Hodoodo Cat#: H205891
Name: Kevetrin HCl
CAS#: 66592-89-0 (HCl)
Chemical Formula: C5H10ClN3S
Exact Mass: 0.00
Molecular Weight: 179.670
Elemental Analysis: C, 33.43; H, 5.61; Cl, 19.73; N, 23.39; S, 17.84
Related CAS #: 66592-89-0 (HCl) 500863-50-3 (free base)
Synonym: Kevetrin; thioureidobutyronitrile; thioureido butyronitrile
IUPAC/Chemical Name: 3-cyanopropyl carbamimidothioate hydrochloride
InChi Key: NCXJZJFDQMKRKM-UHFFFAOYSA-N
InChi Code: InChI=1S/C5H9N3S.ClH/c6-3-1-2-4-9-5(7)8;/h1-2,4H2,(H3,7,8);1H
SMILES Code: NC(SCCCC#N)=N.[H]Cl
Appearance: white 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
More Info: Kevetrin is currently being developed by Cellceutix, who reported a recent study on Kevetrin™. The results show that Kevetrin has potent antitumor activity in several wild type and mutant p53 human tumor xenografts e.g. A549, PC-3, MDA-MB-231, HT-29, NCI-H1975, HCT-15, K-562, LNCaP. Kevetrin is non-genotoxic. DNA damaging drugs result in rapid phosphorylation of H2A.X at Ser 139 by PI3K-like kinases; however, Kevetrin did not induce phosphorylation of H2A.X. Since Kevetrin was well-tolerated in GLP safety pharmacology and toxicity studies. (source: http://cancerres.aacrjournals.org/cgi/content/short/72/8_MeetingAbstracts/2874?rss=1).
| Biological target: | Kevetrin hydrochloride is a small molecule and activator of the tumor suppressor protein p53. |
| In vitro activity: | The effects of prolonged kevetrin exposure were investigated by evaluating cell viability after treatment for 24, 48 and 72 h (Fig. S2). At 48 h, a significant decrease in cell viability was observed in MOLM-13 cells at the highest concentration and in OCI-AML3 cells at 170 and 340 µM (Fig. 3B). A dose-dependent inhibition was also detected in KASUMI-1 and NOMO-1 cells (Fig. 3B). To better define the mechanism of action of kevetrin, apoptosis and cell cycle progression were analyzed. In KASUMI-1 cells, a significant apoptosis induction was observed after 24 h of treatment at the highest concentration (Fig. 3C and Fig. S3). After a 48-h exposure to the highest kevetrin concentration (340 µM), a significant increase was observed in Annexin V+ cells among MOLM-13 (54.95±5.63% in kevetrin-treated cells vs. 12.53±6.15% in the control) and NOMO-1 (60.93±2.63% in kevetrin-treated cells vs. 22.90±4.63% in the control) cells, and a mild but significant effect in OCI-AML3 cells (10.03±3.79% in kevetrin-treated cells vs. 2.60±0.70% in the control; Fig. 3D and Fig. S4). KASUMI-1 cells exhibited a dose-dependent response at 48 h, with 79.70±4.57% of apoptotic cells at 340 µM (compared with 13.18±0.80% in the control; Fig. 3D and Fig. S4). Apoptotic data in MOLM-13 and KASUMI-1 cells were confirmed in terms of mitochondrial depolarization, DNA fragmentation and caspase-3 activation (Fig. S5A-F). No cell cycle alterations were observed in MOLM-13 and KASUMI-1 cells, while NOMO-1 and OCI-AML3 cells displayed an accumulation of cells in the G0/G1 phase and a decrease of S phase cells after 24 and 48 h of kevetrin treatment at any concentration (Fig. 3E and F and Fig. S6A-D). Reference: Oncol Rep. 2020 Oct;44(4):1561-1573. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448420/ |
| In vivo activity: | The animals were implanted Subcutaneously with human breast carcinoma MDA-MB-231, and the compounds were injected IV as per the schedule. Kevetrin administered animals showed greater efficacy than the Taxol treated animals. The tumor growth was delayed 12 days more than the Taxol treated animals and 32 days more than the untreated control. The results are depicted in FIG. 4. Reference: Menon, Krishna. Nitrile derivatives and their pharmaceutical use and compositions. U.S. Pat. Appl. Publ. (2012), US 20120189537 A1. |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 38.0 | 211.50 | |
| Water | 36.0 | 200.37 | |
| Ethanol | 21.0 | 116.88 | |
| PBS (pH 7.2) | 10.0 | 55.66 |
The following data is based on the product molecular weight 179.67 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. Napolitano R, De Matteis S, Carloni S, Bruno S, Abbati G, Capelli L, Ghetti M, Bochicchio MT, Liverani C, Mercatali L, Calistri D, Cuneo A, Menon K, Musuraca G, Martinelli G, Simonetti G. Kevetrin induces apoptosis in TP53 wild‑type and mutant acute myeloid leukemia cells. Oncol Rep. 2020 Oct;44(4):1561-1573. doi: 10.3892/or.2020.7730. Epub 2020 Aug 11. PMID: 32945487; PMCID: PMC7448420. 2. U.S. Pat. Appl. Publ. (2012), US 20120189537 A1. |
| In vitro protocol: | 1. Napolitano R, De Matteis S, Carloni S, Bruno S, Abbati G, Capelli L, Ghetti M, Bochicchio MT, Liverani C, Mercatali L, Calistri D, Cuneo A, Menon K, Musuraca G, Martinelli G, Simonetti G. Kevetrin induces apoptosis in TP53 wild‑type and mutant acute myeloid leukemia cells. Oncol Rep. 2020 Oct;44(4):1561-1573. doi: 10.3892/or.2020.7730. Epub 2020 Aug 11. PMID: 32945487; PMCID: PMC7448420. |
| In vivo protocol: | 1. U.S. Pat. Appl. Publ. (2012), US 20120189537 A1. |
1. Nitrile derivatives and their pharmaceutical use and compositions By Menon, Krishna From U.S. Pat. Appl. Publ. (2012), US 20120189537 A1 20120726.
2. Nitrile derivatives and their pharmaceutical use and compositions By Menon, Krishna From PCT Int. Appl. (2010), WO 2010135170 A2 20101125.
3. Preparation of 4-isothioureido butyronitrile hydrochloride derivatives for treatment of cancer By He, Lan; Pan, Xuan From Faming Zhuanli Shenqing (2009), CN 101550098 A 20091007.
4. Preparation of protein conjugates via intermolecular disulfide bond formation By King, Te Piao; Li, Yen; Kochoumian, Loucia From Biochemistry (1978), 17(8), 1499-506.
5. Preparation of some amino sulfonamides By Miller, Ellis; Sprague, James M.; Kissinger, L. W.; McBurney, Lane F. From Journal of the American Chemical Society (1940), 62, 2099-102.
