CB-1158 analog

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CB-1158 analog
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Size Price Stock
5mg$150To Be Confirmed
10mg$250To Be Confirmed
25mg$450To Be Confirmed
50mg$680To Be Confirmed
100mg$1050To Be Confirmed

Cat #: V3271 CAS #: 1345810-21-0 Purity ≥ 98%

Description: CB-1158 analog (CB-1158, INCB01158 or Numidargistat analog) is a potent and orally bioavailable small-molecule inhibitor of the arginase with potential immunomodulating activities. Myeloid cells are an abundant leukocyte in many types of tumors and contribute to immune evasion. Expression of the enzyme arginase 1 (Arg1) is a defining feature of immunosuppressive myeloid cells and leads to depletion of L-arginine, a nutrient required for T cell and natural killer (NK) cell proliferation. CB-1158 has shown high anti-cancer activity in renal cell cancer, breast cancer, non-small cell lung cancer, acute myeloid leukemia, and other tumor types where arginase-secreting MDSCs are known to play an immunosuppressive role. Arginase blockade by CB-1158 may be an effective therapy in multiple types of cancer, also the combination of CB-1158 with standard-of-care chemotherapy or other immunotherapies that target T-cell activation, such as CTLA-4 and PD-1 antibodies may yield improved clinical responses. CB-1158 is currently in a Phase I clinical trial as a single agent and in combination with immune checkpoint therapy in patients with advanced/metastatic solid tumors.

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Molecular Weight (MW)417.13
Molecular FormulaC18H27BCl2N2O4
CAS No.1345810-21-0
Storage-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility In VitroDMSO: > 10mM
Water: N/A
Ethanol: N/A
SMILES CodeClC1=CC(Cl)=CC=C1CN2CCC(C(N)(CCCCB(O)O)C(O)=O)CC2
SynonymsINCB01158, CB-1158, INCB 01158, CB 1158, INCB-01158; CB1158
ProtocolIn VitroIn vitro activity: CB-1158 (previously known as INCB01158) is a potent and orally-bioavailable small-molecule inhibitor of the arginase. Myeloid cells are an abundant leukocyte in many types of tumors and contribute to immune evasion. Expression of the enzyme arginase 1 (Arg1) is a defining feature of immunosuppressive myeloid cells and leads to depletion of L-arginine, a nutrient required for T cell and natural killer (NK) cell proliferation. CB-1158 has shown high anti-cancer activity in renal cell cancer, breast cancer, non-small cell lung cancer, acute myeloid leukemia, and other tumor types where arginase-secreting MDSCs are known to play an immunosuppressive role. Arginase blockade by CB-1158 may be an effective therapy in multiple types of cancer, also the combination of CB-1158 with standard-of-care chemotherapy or other immunotherapies that target T-cell activation, such as CTLA-4 and PD-1 antibodies may yield improved clinical responses. Kinase Assay: Recombinant human arginase 2 (Arg2) comprising amino acids 23–254 was purchased from US Biological (Salem, MA). Activity assays using 2 nM Arg1 or 4 nM Arg2 were performed in reaction buffer (137 mM NaCl, 2.7 mM KCl, 8 mM Na2HPO4, 2 mM KH2PO4, 0.005% Triton X-100, 0.5 mM DTT, 0.5 mM MgCl2, 0.1 mM CaCl2, and 160 μM or 20 mM L-arginine, pH 7.4) at 37 °C for 30 min with a dose-titration of CB-1158. Activity was determined by a spectrophotometric assay using the QuantiChrom Urea Assay Kit (BioAssay Systems, Hayward, CA) or by quantification of the generation of 13C(5)-L-ornithine from 13C(6)-L-arginine using a SCIEX API4000 mass spectrometer. Urea produced or 13C(5)-L-ornithine peak areas were plotted and fitted to a four-parameter equation using GraphPad Prism software (San Diego, CA) to determine IC50 values. Cell Assay: T cells or NK cells were purified from healthy donor human blood or from murine splenocytes using a negative selection kit for the appropriate cell type and species from Stemcell Technologies. Isolated T cells or NK cells were loaded with carboxyfluorescein succinimidyl ester (CFSE, Thermo Fisher) and stimulated for 72–96 h in complete growth medium containing a minimum of either 50 μM L-arginine (NK cells) or 100 μM L-arginine (T cells). For T cell stimulation, a solution of 10 μg/mL anti-CD3 (human clones UCHT1 or OKT3; murine clone 145-2C11) was used to coat the wells of a 96-well plate and then T cells were stimulated on immobilized anti-CD3 in the presence of 2 μg/mL soluble anti-CD28 (human clone CD28.2; murine clone 37.51). NK cells were stimulated with recombinant IL-2. Proliferation was quantified by analyzing CFSE dilution by flow cytometry.
In VivoFemale wild-type C57BL/6 and Balb/c mice (5–6 weeks old) were purchased from Charles River Laboratories (Hollister, CA). Severe combined immune deficient (SCID, B6.CB17-PrkdcSCID/SzJ) and Pmel-1 TCR transgenic (B6.Cg-Thy1a/Cy Tg(TcraTcrb)8Rest/J) mice (5–6 weeks old) were purchased from The Jackson Laboratory (Bar Harbor, ME). All mice were housed and treated in accordance with Institutional Animal Care and Use Committee guidelines. For the 4T1 tumor model, 105 cells were injected orthotopically into the mammary fat pad; for all other tumor models, 106 cells were injected subcutaneously (s.c.) in the right flank. For all studies, CB-1158 was administered by oral gavage twice per day at 100 mg/kg starting on study day 1 (1 day after tumor implant). Control groups received vehicle (water) twice daily by gavage. Tumor volume measured by digital caliper (length × width × width/2) and body weight were recorded three times per week. Animals were euthanized when tumors necrotized or volumes reached 2000 mm3. For the CT26 model, anti-PD-L1 antibody (5 mg/kg, clone 10F.9G2, BioXCell, West Lebanon, NH) was injected intraperitoneally (i.p.) on days 5, 7, 9, 11, 13, and 15. For the 4T1 model, anti-CTLA-4 antibody (5 mg/kg, clone 9H10, BioXCell) was injected i.p. on days 2, 5, and 8; anti-PD-1 antibody (5 mg/kg, clone RMP1–14, BioXCell) was injected i.p. on days 3, 6, and 9. 4T1 tumors were harvested on study day 25 into Fekete’s solution and tumor nodules were enumerated visually. Gemcitabine was 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. For CD8+ cell depletion, mice were injected i.p. with anti-CD8 antibody (25 mg/kg, clone 2.43, BioXCell) on days −1, 0, + 5, and +10. For NK cell depletion, mice were injected i.p. with anti-NK1.1 antibody (25 mg/kg, clone PK136, BioXCell) in the LLC and B16 models or with anti-Asialo GM1 sera (20 μL) in the CT26 model, per the same schedule as anti-CD8.
Animal modelFemale wild-type C57BL/6 and Balb/c mice (5–6 weeks old)
These protocols are for reference only. InvivoChem does not independently validate these methods.
Preparing Stock Solutions
Solvent volume to be added Mass (the weight of a compound)
Mother liquor concentration 1mg5mg10mg20mg
1mM2.3973 mL11.9867 mL23.9733 mL47.9467 mL
5mM0.4795 mL2.3973 mL4.7947 mL9.5893 mL
10mM0.2397 mL1.1987 mL2.3973 mL4.7947 mL
20mM0.1199 mL0.5993 mL1.1987 mL2.3973 mL
Quality Control Documentation
The molarity calculator equation
Mass(g) = Concentration(mol/L) × Volume(L) × Molecular Weight(g/mol)
Mass
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Volume
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Molecular Weight*
The dilution calculator equation
Concentration(start) × Volume(start) = Concentration(final) × Volume(final)

This equation is commonly abbreviated as: C1 V1 = C2 V2

Concentration(start)
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Step One: Enter information below
Dosage mg/kg Average weight of animals g Dosing volume per animal µL Number of animals
Step Two: Enter the in vivo formulation
%DMSO + % + %Tween 80 + %ddH2O

Calculation Results:
Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in µL DMSO(Master liquid concentration mg/mL) ,Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation: Take µL DMSO master liquid, next add µL PEG300, mix and clarify, next add µL Tween 80,mix and clarify, next add µL ddH2O,mix and clarify.
Note:
  • (1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
  • (2) Be sure to add the solvent(s) in order.