GLS1 Inhibitor III; CB-839 1PC X 10MG

Biochem/physiol Actions

Reversible: yes

Primary TargetGLS1

Cell permeable: yes

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

General description

A cell-permeable thiadiazolyl-butyl-pyridazinyl compound that selectively inhibits GLS1 (IC₅₀ = 23 nM &amp;amp;amp;amp;amp;amp; 28 nM, respectively, using murine kidney and brain homogenates), but not GLS2/LGA (up to 5 &amp;amp;amp;amp;amp;micro;M 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 &amp;amp;amp;amp;amp;amp; &amp;amp;amp;amp;amp;amp; 50 nM/1 h for CB-839; 630 nM/1 min &amp;amp;amp;amp;amp;amp; 700 nM/1 h for BPTES; 2 nM rhGAC aa 126-598) &amp;amp;amp;amp;amp;amp; reversibility (Activity recovery t_{1/2&lt;/sub> after free drug removal = 45 min/CB-839 &amp;amp;amp;amp;amp;amp; &lt;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 &amp;amp;amp;amp;amp;micro;M with BPTES; GI50 against HCC1806 in 72 h = 55 nM vs. 2.0 &amp;amp;amp;amp;amp;micro;M with BPTES), while neither drug is effective against GLS1-independent growth of estrogen receptor-positive T47D even at 1 &amp;amp;amp;amp;amp;micro;M concentration. Despite a fast clearance in mice (Plasma t1/2&lt;/sub><2 h post 50 mg/kg p.o.), good drug exposure is reported in tumor and major organs (&gt;1 nmol/g) 4 h post single 200 mg/10 mL/kg oral dosage among HCC1806 xenograft mice (Drug conc. = 2.1 &amp;amp;amp;amp;amp;micro;M in Plasma &amp;amp;amp;amp;amp;amp; 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 &amp;amp;amp;amp;amp;amp; 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.

Legal Information

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

Other Notes

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

Packaging

Packaged under inert gas

10 mg in Glass bottle

Reconstitution

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

Warning

Toxicity: Standard Handling (A)