In vitro: CB-839 exhibits time-dependent and slowly reversible kinetics. IC50 values for glutaminase inhibition by CB-839 following preincubation with rHu-GAC for-1 hour are < 50 nmol/L, at least 13-fold lower than with BPTES. CB-839 has antiproliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, while no antiproliferative activity is observed in an estrogen receptor–positive cell line, T47D.
In vivo: In the mouse TNBC model, single agent CB-839 (200 mg/kg, p.o.) suppresses tumor growth by 61% relative to vehicle control. In the mouse JIMT-1 xenograft model, CB-839 alone (200 mg/kg, p.o.) results in 54% tumor growth inhibition (TGI) relative to vehicle control, combination of CB-839 (200 mg/kg, p.o.) with paclitaxel (10 mg/kg, p.o.) largely suppresses the regrowth of the tumors resulting in a TGI relative to vehicle control of 100%.
|Cell lines||HCC1806, MDA-MB-231, and T47D cells|
|Preparation method||For viability assays, all cell lines are treated with CB-839 at the indicated concentrations for 72 hours and analyzed for antiproliferative effects using Cell Titer Glo.|
|Incubation time||72 h|
|Animal models||Female Scid/Bg mice bearing TNBC or JIMT-1 xenograft|
|Formulation||25% (w/v) hydroxypropyl-b-cyclodextrin (HPBCD) in 10 mmol/L citrate, pH 2|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||80 mg/mL warmed in DMSO|
Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition.
Jacque N, et al. Blood. 2015 Sep 10;126(11):1346-56. PMID: 26186940.
Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer.
Gross MI, et al. Mol Cancer Ther. 2014 Apr;13(4):890-901. PMID: 24523301.
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