6-amino-1,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
6-amino-1,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile Basic information
- Product Name:
- 6-amino-1,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
- Synonyms:
-
- BQU57
- 6-amino-1,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
- BQU57, >98%
- CS-2300
- Pyrano[2,3-c]pyrazole-5-carbonitrile, 6-amino-1,4-dihydro-1,3-dimethyl-4-[4-(trifluoromethyl)phenyl]-
- BQU57 >=98% (HPLC)
- BQU57,inhibit,BQU-57,Ras,Inhibitor,BQU 57
- BQU57, 10 mM in DMSO
- CAS:
- 1637739-82-2
- MF:
- C16H13F3N4O
- MW:
- 334.3
- Product Categories:
-
- Inhibitors
- Mol File:
- 1637739-82-2.mol
6-amino-1,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile Chemical Properties
- Boiling point:
- 493.4±45.0 °C(Predicted)
- Density
- 1.43±0.1 g/cm3(Predicted)
- storage temp.
- Store at -20°C
- solubility
- insoluble in H2O; ≥16.55 mg/mL in DMSO; ≥9.2 mg/mL in EtOH
- form
- solid
- pka
- 2.92±0.40(Predicted)
- color
- Light yellow to yellow
6-amino-1,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile Usage And Synthesis
Uses
BQU57 ia a novel blocker of Ral function.
Biological Activity
bqu57 is a derivative of rbc8. it show selectivity for ral relative to the gtpases ras and rhoa and inhibit tumour xenograft growth. the binding of bqu57 to ralb–gdp was with a dissociation constant (kd) of 7.760.6 mm by using isothermal titration calorimetry (itc). it was similar to the results from surface plasmon resonance (spr), which had a kd value of 4.761.5 mm 1.rbc8 or bqu57 can effectively inhibited the colony formation in soft agar of the ral-dependent lines h2122 and h358, but not h460 or calu-6. the ic50 value of rbc8 was 3.5 mm in h2122 cells and 3.4 mm in h358 cells; and the ic50 value of bqu57 was 2.0 mm in h2122 cells and 1.3 mm in h358 cells. rbc8 or bqu57 treatment showed no further inhibition of colony formation after ral knockdown 1.rbc8 and bqu57 acted specifically through the gdp-bound form of ral proteins. rbc8 and bqu57 inhibited both ral a and ral b activation in both the h2122 and h358 cell lines by a ral pull-down assay using ralbp1-bound agarose beads 1.the inhibition of ral activity and tumour growth by these compounds were evaluated in human lung cancer xenografts in mice. rbc8 and bqu57 showed good properties in vivo. rbc8 and bqu57 entry into tumour tissue 3 h after dosing, and were detectable in tumour tissue 1. bqu57 (10, 20 and 50mg per kg bodyweight) was intraperitoneal injected into h2122 tumour xenografts, and the activation of ral in tumour extracts was analysed in ralbp1 pull-down assays. both rala and ralb were inhibited by rbc8 and bqu57. but no inhibition of ras or rhoa activity was happened 1.
in vivo
BQU57 (1 mg/kg and 5 mg/kg; ip; once a day; 6 weeks) significantly alleviated lumbar instability-induced disc degeneration in rats, reduced nucleus pulposus cell apoptosis and maintained disc structural integrity[2].
BQU57 (50 mg/kg; ip; 3 times a week; 21 days) significantly inhibited orthotopic tumor growth and lung metastasis in mice with triple-negative breast cancer (TNBC) and prolonged survival[3].
| Animal Model: | C57BL/6J mice (male, 8-week-old) with lumbar instability-induced intervertebral disc degeneration[2] |
| Dosage: | 1 mg/kg and 5 mg/kg (dissolved in 0.9% saline) |
| Administration: | Intraperitoneal injection daily for 6 weeks |
| Result: | Reduced disc height loss (X-ray analysis) and histological degeneration (Safranin O-Fast Green staining). Decreased apoptosis (TUNEL assay) and downregulated pro-inflammatory markers (MMP-13, NF-κB p65) in nucleus pulposus tissues in Immunohistochemistry assay. |
| Animal Model: | NSG mice (female, 6-8-week-old) with orthotopic MDA-MB-231 TNBC xenografts[3] |
| Dosage: | 50 mg/kg (dissolved in DMSO) |
| Administration: | Intraperitoneal injection 3×/week until tumor resection criteria met (average 21 days) |
| Result: | Significantly reduced primary tumor growth (average volume: 385 mm3 vs. 720 mm3 in controls) and spontaneous lung metastasis (75% reduction in metastatic area). Decreased RalA/B activation and NF-κB signaling in tumor tissues in WB assay. |
| Animal Model: | FVB/N mice (female, 6-8-week-old) with MVT1 murine TNBC orthotopic tumors[3] |
| Dosage: | 50 mg/kg (dissolved in DMSO) |
| Administration: | Intraperitoneal injection 3×/week for 21 days |
| Result: | Delayed tumor progression (median survival: 42 days vs. 30 days in controls) and reduced experimental lung metastasis (bioluminescence imaging). Revealed decreased Ki67 proliferation and increased cleaved caspase-3 apoptosis in tumors in Immunohistochemistry assay. |
| Animal Model: | NSG mice (female, 11-week-old) with TNBC patient-derived xenografts (PDX-TM00096)[3] |
| Dosage: | 50 mg/kg (dissolved in DMSO) |
| Administration: | Intraperitoneal injection 3×/week for 24 days |
| Result: | Significantly inhibited PDX tumor growth (average volume: 220 mm3 vs. 550 mm3 in controls) with minimal toxicity (body weight loss <5%). Reduced RalA/B activation and ECM degradation markers in tumor tissues. |
References
1. yan c, liu d, li l et al. discovery and characterization of small molecules that target the gtpase ral. nature. 2014 nov 20;515(7527):443-7.
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