生物活性

• 靶点	Glutaminase kidney-type IC50:24nM

• 描述Glutamine is one of fuels for the growth of many cancers and can be conversed to glutamate by the mitochondrial glutaminase including KGA and GAC. CB-839 is a potent, selective, and orally bioavailable inhibitor of the two glutaminase with IC50 value less than 50nM in recombinant human GAC (rHu-GAC) and with Ki ranging from 0.2 to 3μM. Treatment of HCC1806 and MDA-MB-231 cells with CB-839 demonstrated its potent effect on the proliferation with IC50 values of 20-55nM but not affect the viability of T47D cells. Meanwhile, 1 μM CB-839 could completely inhibited glutamine consumption rate in HCC1806 cells accompanied by dramatically reduction of glutamate production rates. Specially, the glutamine consumption rate was partially inhibited in T47D cells and glucose consumption or lactate production rates were not impacted in both cell lines. Treatment of this drug also reduced the concentration of the key metabolites downstream of glutamate without effecting on cellular glucose levels including aspartate, glutathione and the TCA cycle intermediates, etc., suggesting a possibly impairment of mitochondrial function when ATP synthase dependent oxygen consumption was reduced. The mRNA expressions analysis of GAC, KGA, GLS2 and GLUL demonstrated high levels of both GAC and KGA and a variable unclear distinction of GLUL and GLS2. In addition, a panel of 28 breast cancer cell lines were treated with CB-839 and displayed antiproliferative IC50 values ranging from 2 to 300 nM. Treatment with 200 mg/kg CB-839 could also suppressed tumor growth by 61% in patient-derived TNBC model^[1]. In GLS-knockdown MDA-MB-231 cells, CB-839 at concentrations ranging from 0.1 to 10 μM led to accumulation of ATF4 protein. In U-2 OS cell line, a decrease in the levels of phospho-P70 S6K (Thr 389) was also observed with this drug treatment^[2].
• 作用机制CB-839 can allosteric bind to glutaminase in a kinetic, slow-on / slow-off behavior ^[1].

• 动物研究
  剂量	Mice: 200 mg/kg[3] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03057600	Triple Negative Breast Cancer ... more >> TNBC - Triple-Negative Breast Cancer Collapse <<	Phase 2	Active, not recruiting	May 1, 2020	-
  NCT03428217	Advanced Renal Cell Carcinoma ... more >> Metastatic Renal Cell Carcinoma Collapse <<	Phase 2	Recruiting	June 30, 2022	-
  NCT03263429	Colorectal Cancer ... more >> Metastatic Colorectal Cancer RAS Wild Type Colorectal Cancer Refractory Colorectal Cancer Collapse <<	Phase 1 Phase 2	Recruiting	August 2021	United States, Tennessee ... more >> Vanderbilt-Ingram Cancer Center Recruiting Nashville, Tennessee, United States, 37232 Contact: Clinical Trials Information Program    800-811-8480       Principal Investigator: Jordan Berlin, MD Collapse <<

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• 参考文献

• [1] Gross MI, Demo SD, et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014;13(4):890-901.

  [2] Lampa M, Arlt H, et al. Glutaminase is essential for the growth of triple-negative breast cancer cells with a deregulated glutamine metabolism pathway and its suppression synergizes with mTOR inhibition. PLoS One. 2017;12(9):e0185092.