533717 GLS1 Inhibitor III, CB-839 - CAS 1439399-58-2 - Calbiochem

533717
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      Overview

      Replacement Information

      Key Specifications Table

      Empirical FormulaCAS #
      C₂₆H₂₄F₃N₇O₃S 1439399-58-2

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          Glass bottle 10 mg
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          Description
          OverviewA cell-permeable, orally available thiadiazolyl-butyl-pyridazinyl compound that acts as a potent, selective, time-dependent, and slowly-reversible (t1/2 = 45 min at 25 °C) inhibitor of glutaminase (IC50 = 45, 23 and 28 nM for rec hu-GAC, KGA and GAC, respectively). The inhibition appears to be non-competitive and allosteric. Exhibits anti-proliferative effects in HCC1806 and MDA-MB-231 triple-negative breast cancer cell lines (IC50 = 49 and 26 nM, respectively), but does not affect the viability of ER+/HER2-T47D cell line. Shown to reduce glutamine consumption (IC50 = 17 nM) and glutamate production (IC50 = 15 nM) rates in HCC1806 cells. Inhibits the growth of HCC1806 xenografts in mice (~200 mg/kg, p.o., b.i.d) and of JIMT-1 xenografts (200 mg/kg p.o., b.i.d), either alone or in combination with paclitaxel (10 mg/kg , 5 doses alternate days).

          Please note that the molecular weight for this compound is batch-specific due to variable water content. Please refer to the vial label or the certificate of analysis for the batch-specific molecular weight. The molecular weight provided represents the baseline molecular weight without water.
          Catalogue Number533717
          Brand Family Calbiochem®
          SynonymsN-(6-(4-(5-((2-Pyridin-2-ylacetyl)amino)-1,3,4-thiadiazol-2-yl)butyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide, KGA Inhibitor III, 2-(Pyridin-2-yl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide, GAC Inhibitor III, Kidney-Type Glutaminase Inhibitor III
          DescriptionGLS1 Inhibitor III, CB-839
          References
          ReferencesGross, M.I., et al. 2014. Mol. Cancer Ther. 13, 890.
          Product Information
          CAS number1439399-58-2
          FormYellow solid
          Hill FormulaC₂₆H₂₄F₃N₇O₃S
          Chemical formulaC₂₆H₂₄F₃N₇O₃S
          ReversibleY
          Applications
          Biological Information
          Primary TargetGLS1
          Primary Target IC<sub>50</sub>23 nM & 28 nM, respectively, using murine kidney and brain homogenates
          Purity≥97% by HPLC
          Physicochemical Information
          Cell permeableY
          Dimensions
          Materials Information
          Toxicological Information
          Safety Information according to GHS
          Safety Information
          Product Usage Statements
          Storage and Shipping Information
          Ship Code Ambient Temperature Only
          Toxicity Standard Handling
          Storage +2°C to +8°C
          Protect from Light Protect from light
          Do not freeze Ok to freeze
          Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.
          Packaging Information
          Packaged under inert gas Packaged under inert gas
          Transport Information
          Supplemental Information
          Specifications

          Documentation

          GLS1 Inhibitor III, CB-839 - CAS 1439399-58-2 - Calbiochem SDS

          Title

          Safety Data Sheet (SDS) 

          References

          Reference overview
          Gross, M.I., et al. 2014. Mol. Cancer Ther. 13, 890.
          Data Sheet

          Note that this data sheet is not lot-specific and is representative of the current specifications for this product. Please consult the vial label and the certificate of analysis for information on specific lots. Also note that shipping conditions may differ from storage conditions.

          Revision24-June-2016
          SynonymsN-(6-(4-(5-((2-Pyridin-2-ylacetyl)amino)-1,3,4-thiadiazol-2-yl)butyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide, KGA Inhibitor III, 2-(Pyridin-2-yl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide, GAC Inhibitor III, Kidney-Type Glutaminase Inhibitor III
          DescriptionA cell-permeable thiadiazolyl-butyl-pyridazinyl compound that selectively inhibits GLS1 (IC50 = 23 nM & 28 nM, respectively, using murine kidney and brain homogenates), but not GLS2/LGA (up to 5 µM using murine liver homogenates), glutaminase activity in a non-competitive manner, being more potent than the uncompetitive GLS1 inhibitor BPTES, but with much slower inhibition kinetics (IC50/preincubation time ~300 nM/1 min & & 50 nM/1 h for CB-839; 630 nM/1 min & 700 nM/1 h for BPTES; 2 nM rhGAC aa 126-598) & reversibility (Activity recovery t1/2 after free drug removal = 45 min/CB-839 & <3 min/BPTES). CB-839 also displays higher antiproliferation potency than BPTES against triple negative breast cancer (TNBC) cultures (GI50 against MDA-MB-231 in 72 h = 19 nM vs. 2.4 µM with BPTES; GI50 against HCC1806 in 72 h = 55 nM vs. 2.0 µM with BPTES), while neither drug is effective against GLS1-independent growth of estrogen receptor-positive T47D even at 1 µM concentration. Despite a fast clearance in mice (Plasma t1/2 <2 h post 50 mg/kg p.o.), good drug exposure is reported in tumor and major organs (>1 nmol/g) 4 h post single 200 mg/10 mL/kg oral dosage among HCC1806 xenograft mice (Drug conc. = 2.1 µM in Plasma & 1.5 nmol/g in 500 mm3 tumor) except brain (~0.2 nmol/g) with most pronounced Glutamine buildup observed in tumor (5-fold) when compared to normal tissues (1- to 2.28-fold of of no treatment controls). Twice daily oral administration (200 mg/kg/12 h) is efficacious in suppressing the expansion of established tumor derived from HIMT-1 (by 54% in 35 d) and patient TNBC (by 59% in 28 d) and complete suppression of JIMT-1 tumor is seen when combined with 5 daily doses of Paclitaxel (10 mg/kg i.v.; Cat. Nos. 580555 & 580556) in the first 5 d of the treatment period.
          FormYellow solid
          Intert gas (Yes/No) Packaged under inert gas
          CAS number1439399-58-2
          Chemical formulaC₂₆H₂₄F₃N₇O₃S
          Purity≥97% by HPLC
          SolubilityDMSO (25 mg/ml)
          Storage +2°C to +8°C
          Protect from light
          Do Not Freeze Ok to freeze
          Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.
          Toxicity Standard Handling
          ReferencesGross, M.I., et al. 2014. Mol. Cancer Ther. 13, 890.