CB-839

Description

CB-839 is a potent, selective, and orally bioavailable glutaminase inhibitor with IC50 of 24 nM for recombinant human GAC. Phase 1.

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%.

Description

CB-839 (14393999-58-2)?is a potent (IC50?= 24 nM), selective and orally bioavailable inhibitor of glutaminase (KGA and GAC).1?CB-839 displayed an antiproliferative effect in the triple-negative breast cancer cell line, HCC-1806, but no activity in the estrogen receptor-positive cell line T47D.? CB-839 was able to cause proliferation arrest and apoptosis in acute myeloid leukemia cells without causing cytotoxicity against normal human CD34(+) progenitors.2? Aspartate-glutamate carrier 1 (AGC1) inhibition can synergize with CB-839 to limit tumor growth.3

Uses

CB-839 performs an antileukemic activity. It Inhibits GLS1 genes and reduces oxidative phosphorylation leading to leukamic cell proliferation arrest and apoptosis.

in vivo

storage

Store at -20°C

References

1) Gross?et al. (2014),?Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer; Mol. Cancer Ther.,13?890 2) Jacque?et al. (2015),?Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition; Blood,?126?1346 3) Alkan?et al.?(2018)?Cytosolic Aspartate Availability Determines Cell Survival When Glutamine is Limiting; Cell Metabolism?28?1