5.33717

GLS1 Inhibitor III, CB-839

• Synonym(s): GLS1 Inhibitor III, CB-839, N-(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
• Empirical Formula (Hill Notation): C₂₆H₂₄F₃N₇O₃S
• CAS Number: 1439399-58-2
• Molecular Weight: 571.57
• UNSPSC Code: 12352200

Properties

• Assay: ≥97% (HPLC)
• Quality Level: 100
• form: solid
• manufacturer/tradename: Calbiochem^®
• storage condition: OK to freeze; protect from light
• color: yellow
• solubility: DMSO: 25 mg/mL
• storage temp.: 2-8°C
• InChI: 1S/C26H24F3N7O3S/c27-26(28,29)39-20-9-5-6-17(14-20)15-22(37)31-21-12-11-18(33-34-21)7-1-2-10-24-35-36-25(40-24)32-23(38)16-19-8-3-4-13-30-19/h3-6,8-9,11-14H,1-2,7,10,15-16H2,(H,31,34,37)(H,32,36,38)
• InChI key: PRAAPINBUWJLGA-UHFFFAOYSA-N

Description

General description

A 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 t_1/2 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 t_1/2<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.

A cell-permeable, orally available thiadiazolyl-butyl-pyridazinyl compound that acts as a potent, selective, time-dependent, and slowly-reversible (t_1/2 = 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.

Biochem/physiol Actions

Cell permeable: yes

Primary Target
GLS1

Reversible: yes

Target IC₅₀: 23 nM & 28 nM, respectively, using murine kidney and brain homogenates

Packaging

Packaged under inert gas

Warning

Toxicity: Standard Handling (A)

Reconstitution

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.

Other Notes

Gross, M.I., et al. 2014. Mol. Cancer Ther.13, 890.

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Safety Information

• Storage Class Code: 11 - Combustible Solids
• WGK: WGK 3
• Flash Point(F): Not applicable
• Flash Point(C): Not applicable