1. Immunology/Inflammation
    Metabolic Enzyme/Protease
  2. Arginase

CB-1158 Hydrochloride (Synonyms: INCB01158 Hydrochloride)

Cat. No.: HY-101979A Purity: >98.0%
Handling Instructions

CB-1158 Hydrochloride is a potent and orally bioavailable inhibitor of arginase, with IC50s of 86 and 296 nM for recombinant human arginase 1 and 2, respectively.

For research use only. We do not sell to patients.

CB-1158 Hydrochloride Chemical Structure

CB-1158 Hydrochloride Chemical Structure

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Estimated Time of Arrival: December 31
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Estimated Time of Arrival: December 31
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Estimated Time of Arrival: December 31
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Description

CB-1158 Hydrochloride is a potent and orally bioavailable inhibitor of arginase, with IC50s of 86 and 296 nM for recombinant human arginase 1 and 2, respectively.

IC50 & Target

IC50: 86 nM (Arginase 1), 296 nM (Arginase 2)[1]

In Vitro

CB-1158 Hydrochloride is a potent and orally-bioavailable inhibitor of arginase, with IC50s of 86 and 296 nM for recombinant human arginase 1 and 2, respectively. CB-1158 inhibits native rginase 1 (Arg1) in human granulocyte, erythrocyte, and hepatocyte lysate with IC50s of 178 nM, 116 nM and 158 nM, respectively, and blocks Arg1 in cancer patient plasma (IC50, 122 nM). CB-1158 also exhibits potent inhibitory activity against arginase in human HepG2, K562 cell lines and primary human hepatocytes with IC50s of 32, 139, 210 μM, respectively. CB-1158 show no effect on NOS. In addition, CB-1158 is not directly cytotoxic to murine cancer cell lines[1].

In Vivo

CB-1158 (100 mg/kg, p.o., twice per day) increases the number of tumor-infiltrating cytotoxic cells and decreases myeloid cells in mice. CB-1158 in combination with PD-L1 blockade or gemcitabine inhibits tumor growth in mice bearing CT26 cancer cells[1].

Solvent & Solubility
In Vitro: 

H2O : ≥ 50 mg/mL

DMSO : < 1 mg/mL (insoluble or slightly soluble)

*"≥" means soluble, but saturation unknown.

References
Cell Assay
[1]

Intracellular arginase activity is determined for the arginase-expressing HepG2 and K-562 cell lines as follows. HepG2 cells are seeded at 100,000 cells per well one day prior to treatment with CB-1158. K-562 cells are seeded at 200,000 cells per well on the day of CB-1158 treatment. Cells are treated with a dose-titration of CB-1158 in SILAC RPMI-1640 media containing 5% heat-inactivated and dialyzed FBS, antibiotics/anti-mycotic, 10 mM L-arginine, 0.27 mM L-lysine, and 2 mM L-glutamine. The medium is harvested after 24 h and urea generated is determined. Wells containing media without cells are used as background controls. For assessing the effect of CB-1158 on Arg1 in primary hepatocytes, frozen human hepatocytes are thawed, allowed to adhere onto collagen-coated wells for 4 h, and then incubated for 48 h in SILAC-RPMI containing 10 mM L-ornithine, no L-arginine, and a dose-titration of CB-1158, at which time the media are analyzed for urea[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

Mice[1]
For the 4T1 tumor model, 105 cells are injected orthotopically into the mammary fat pad; for all other tumor models, 106 cells are injected subcutaneously (s.c.) in the right flank. For all studies, CB-1158 is administered by oral gavage twice per day at 100 mg/kg starting on study day 1 (1 day after tumor implant). Control groups receive vehicle (water) twice daily by gavage. Tumor volume measured by digital caliper (length × width × width/2) and body weight are recorded three times per week. Mice are euthanized when tumors necrotize or volumes reach 2000 mm3. For the CT26 model, anti-PD-L1 antibody (5 mg/kg) is injected intraperitoneally (i.p.) on days 5, 7, 9, 11, 13, and 15. For the 4T1 model, anti-CTLA-4 antibody (5 mg/kg) is injected i.p. on days 2, 5, and 8; anti-PD-1 antibody (5 mg/kg) is injected i.p. on days 3, 6, and 9. 4T1 tumors are harvested on study day 25 into Fekete’s solution and tumor nodules are enumerated visually. Gemcitabine is dosed 50 mg/kg i.p. on days 10 and 16 for the CT26 model, 60 mg/kg i.p. on days 6 and 10 for the LLC model, or 30 mg/kg i.p. on day 5 for the 4T1 model. With these regimens, gemcitabine modestly reduces tumor growth and spares most tumor-infiltrating immune cells, allowing for the evaluation of combination activity with CB-1158[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Formula

C₁₁H₂₂BN₃O₅.xHCl

SMILES

O=C([[email protected]@H](N)C)N1C[[email protected]](CCCB(O)O)[[email protected]](N)(C(O)=O)C1.[.xHCl]

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Purity: >98.0%

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CB-1158 Hydrochloride
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CB-1158 Hydrochloride

Cat. No.: HY-101979A