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Purity: ≥98%
ML216 (formerly known as CID-49852229) is a novel potent inhibitor of the Bloom's syndrome protein (BLM) helicase which is responsible for DNA unwinding activity. The results indicated that the IC50s for full length BLM and BLM636–1298 were 3.0 and 0.97 μM, respectively. The conserved RecQ helicase family includes the Bloom's syndrome protein, BLM. While there are cell lines with no BLM, these show progressive genomic instability, making it difficult to separate the primary from secondary effects of BLM loss. ML216 exhibits cell-based activity and is able to promote the toxicity of aphidicolin, cause sister chromatid exchanges, and inhibit the proliferation of cells that express BLM but not those that do not. According to these findings, ML216 exhibits a high degree of BLM selectivity in cultured cells. ML216 thus has the potential to be useful as an anticancer agent because it targets BLM.
| Targets |
BLMfull-length ( IC50 = 2.98 μM ); BLM636-1298 ( IC50 = 0.97 μM )
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| ln Vitro |
ML216 (12.5-50 μM; 24-72 hours; PSNG5 and PSNG13cells) treatmentsuppresses PSNF5 cell proliferation, but not PSNG13 cell proliferation in a concentration-dependent manner[1].
ML216 treatment increases the frequency of sister chromatid exchanges (SCEs) in a statistically significant way in PSNF5 cells, but not in PSNG13 cells[1]. ML216 enhances the aphidicolin sensitivity of PSNF5 cells, but has no sensitizing effect on isogenic PSNG13 cells lacking BLM[1]. ML216 inhibits WRN500-946 (IC50 of 12.6 μM), which is 2.5 times more sensitive to inhibition than the full length WRN (IC50 of 5 μM). Based on IC50 values, BLM is slightly more sensitive than WRN to ML216's inhibition (1.7-fold). Even though ML216 clearly inhibits WRN, this substance seems to be specific to BLM in human cells. Both WRN+ and WRN? cell proliferation is equally inhibited by ML216, and both cell types are similarly sensitized to aphidicolin[1]. |
| ln Vivo |
Though ML216 inhibits unwinding by the sequence-related BLM and WRN helicases in vitro in a manner similar to that of WRN helicases, the drug's mechanism of action in vivo appears to be specific for BLM based on ML216's apparent reliance on BLM for biological effects in human cells. Informational would be a co-crystal structure of BLM in complex with the inhibitor. A certain conformation of WRN that renders it resistant to ML216 may be induced by cellular cues in vivo[2].
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| Cell Assay |
Cell Line: PSNG5 and PSNG13cells
Concentration: 12.5 μM or 50 µM Incubation Time: 24 hours, 48 hours, 72 hours Result: Inhibited the proliferation of PSNF5 cells, but not of PSNG13 cells, and did so in a concentration-dependent manner. |
| References | |
| Additional Infomation |
1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-(5-pyridin-4-yl-1,3,4-thiadiazol-2-yl)urea is a member of ureas.
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| Molecular Formula |
C15H9F4N5OS
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| Molecular Weight |
383.32
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| Exact Mass |
383.046
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| Elemental Analysis |
C, 47.00; H, 2.37; F, 19.82; N, 18.27; O, 4.17; S, 8.36
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| CAS # |
1430213-30-1
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| Related CAS # |
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| PubChem CID |
49852229
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.6±0.1 g/cm3
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| Index of Refraction |
1.641
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| LogP |
4.11
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
26
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| Complexity |
491
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(NC1=CC=C(F)C(C(F)(F)F)=C1)NC2=NN=C(S2)C3=CC=NC=C3
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| InChi Key |
WMCOYUSJXXCHFH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C15H9F4N5OS/c16-11-2-1-9(7-10(11)15(17,18)19)21-13(25)22-14-24-23-12(26-14)8-3-5-20-6-4-8/h1-7H,(H2,21,22,24,25)
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| Chemical Name |
1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-(5-pyridin-4-yl-1,3,4-thiadiazol-2-yl)urea
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2 mg/mL (5.22 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6088 mL | 13.0439 mL | 26.0879 mL | |
| 5 mM | 0.5218 mL | 2.6088 mL | 5.2176 mL | |
| 10 mM | 0.2609 mL | 1.3044 mL | 2.6088 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
(A) Structure of MLS000559245 that was identified during the high throughput screen and ML216, which was developed through subsequent medicinal chemistry optimization of this chemotype. (B) Effects on ML216 on the helicase activity of BLM636–1298and full-length BLM. In the absence of ML216, BLM unwinds the forked duplex into ssDNA (depicted diagrammatically on the right). The open triangle above the left lane in each case depicts heat-denatured DNA. The asterisk denotes fluorescent-end label. (C) Quantification of the extent of BLM inhibition by ML216.Chem Biol.2013 Jan 24;20(1):55-62. |
(A) Effect of ML216 on binding BLM to ssDNA or a forked duplex using EMSA. Data were derived from 2 independent gel retardation experiments. Error bars: SE. (B) As in panel A, except effects on DNA binding measured using fluorescence polarization (FP).Chem Biol.2013 Jan 24;20(1):55-62. |
ML216 has activity in human cells that depends on BLM. (A, B) Effects of different concentrations of ML216, as indicated, on the rate of cell proliferation in PSNF5 (BLM+; panel A) and PSNG13 (BLM−; panel B) cells.
(A) ML216 sensitizes PSNF5, but not PSNG13, cells to aphidicolin.(B) ML216 suppresses γ-H2AX focus formation in MMC-treated PSNF5 cells, but not similarly treated PSNG13 cells.Chem Biol.2013 Jan 24;20(1):55-62. |
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