GLS1 INHIBITOR III CB-839

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