Ciforadenant
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MedKoo CAT#: 206846

CAS#: 1202402-40-1

Description: Ciforadenant, also known as CPI-444 and V81444, is an orally administered antagonist of the adenosine A2A receptor. Upon oral administration, CPI-444 binds to adenosine A2A receptors expressed on the surface of immune cells, including T-lymphocytes, natural killer (NK) cells, macrophages and dendritic cells (DCs). This prevents tumor-released adenosine from interacting with the A2A receptors on these key immune surveillance cells, thereby abrogating adenosine-induced immunosuppression in the tumor microenvironment.


Chemical Structure

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Ciforadenant
CAS# 1202402-40-1

Theoretical Analysis

MedKoo Cat#: 206846
Name: Ciforadenant
CAS#: 1202402-40-1
Chemical Formula: C20H21N7O3
Exact Mass: 407.17
Molecular Weight: 407.434
Elemental Analysis: C, 58.96; H, 5.20; N, 24.07; O, 11.78

Price and Availability

Size Price Availability Quantity
5mg USD 90 Ready to ship
10mg USD 150 Ready to ship
25mg USD 250 Ready to ship
25mg USD 450 Ready to ship
100mg USD 750 Ready to ship
500mg USD 2850 Ready to Ship
1g USD 4250 Ready to ship
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Related CAS #: 1202402-40-1   1202402-47-8 (R-isomer)   2102305-11-1 (racemic)    

Synonym: CPI-444; CPI 444; CPI444; V81444; V-81444; V 81444; ciforadenant;

IUPAC/Chemical Name: (S)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

InChi Key: KURQKNMKCGYWRJ-HNNXBMFYSA-N

InChi Code: InChI=1S/C20H21N7O3/c1-12-5-6-16(30-12)17-18-19(24-20(21)23-17)27(26-25-18)9-13-3-2-4-14(22-13)10-29-15-7-8-28-11-15/h2-6,15H,7-11H2,1H3,(H2,21,23,24)/t15-/m0/s1

SMILES Code: NC1=NC2=C(N=NN2CC3=NC(CO[C@H]4CCOC4)=CC=C3)C(C5=CC=C(O5)C)=N1

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Biological target: CPI-444 (V81444) is an adenosine A2A receptor (A2AR) antagonist.
In vitro activity: Activated T cells have high expression of A2AR, and NECA-mediated activation of A2AR increased cAMP in human T cells (Fig. 2A), consistent with previous reports (13, 36–38). Inclusion of CPI-444 led to a dose-dependent inhibition of the production of intracellular cAMP following stimulation of activated primary human T cells with NECA (IC50 = 70 nmol/L; Fig. 2A). CPI-444 completely inhibited NECA-mediated elevation of cAMP in these human PBMC cultures, suggesting that A2AR is the dominant adenosine receptor that mediates immune suppression in this system. Elevated intracellular cAMP following A2AR activation results in the phosphorylation of CREB (cAMP response element-binding protein; ref. 39). CPI-444 treatment inhibited phosphorylation of CREB (pCREB; Supplementary Fig. S1A) in NECA-stimulated cells. These results demonstrate that CPI-444 restores T-cell signaling in the presence of adenosine analogues. Reference: Cancer Immunol Res. 2018 Oct;6(10):1136-1149. https://cancerimmunolres.aacrjournals.org/content/6/10/1136.long
In vivo activity: MC38 is a mouse colon carcinoma cell line that is responsive to immune checkpoint blockade, including anti–PD-1 antibodies (28, 29). To evaluate the antitumor efficacy of CPI-444 in vivo, MC38 cells were engrafted onto the backs of syngeneic C57BL/6 mice. One day after tumor cell engraftment, vehicle control solution or CPI-444 (1, 10, or 100 mg/kg) was administered daily via oral gavage for 28 days (see Supplementary Table S2 for details of all animal experiments). Administration of CPI-444 at 10 mg/kg and 100 mg/kg resulted in a significant inhibition of tumor growth, whereas 1 mg/kg had no discernable effect compared with vehicle-treated animals (Fig. 3A and Supplementary Fig. S2A–S2C for spider plots of individual mice). Complete tumor regression was observed in 9 of 29 mice treated with CPI-444 (Supplementary Fig. S2D). Tumor growth was fully inhibited when mice with cleared tumors were later rechallenged, indicating that CPI-444 induced systemic antitumor immune memory. Reference: Cancer Immunol Res. 2018 Oct;6(10):1136-1149. https://cancerimmunolres.aacrjournals.org/content/6/10/1136.long

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 74.3 182.24

Preparing Stock Solutions

The following data is based on the product molecular weight 407.43 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Willingham SB, Ho PY, Hotson A, Hill C, Piccione EC, Hsieh J, Liu L, Buggy JJ, McCaffery I, Miller RA. A2AR Antagonism with CPI-444 Induces Antitumor Responses and Augments Efficacy to Anti-PD-(L)1 and Anti-CTLA-4 in Preclinical Models. Cancer Immunol Res. 2018 Oct;6(10):1136-1149. doi: 10.1158/2326-6066.CIR-18-0056. Epub 2018 Aug 21. PMID: 30131376.
In vitro protocol: 1. Willingham SB, Ho PY, Hotson A, Hill C, Piccione EC, Hsieh J, Liu L, Buggy JJ, McCaffery I, Miller RA. A2AR Antagonism with CPI-444 Induces Antitumor Responses and Augments Efficacy to Anti-PD-(L)1 and Anti-CTLA-4 in Preclinical Models. Cancer Immunol Res. 2018 Oct;6(10):1136-1149. doi: 10.1158/2326-6066.CIR-18-0056. Epub 2018 Aug 21. PMID: 30131376.
In vivo protocol: 1. Willingham SB, Ho PY, Hotson A, Hill C, Piccione EC, Hsieh J, Liu L, Buggy JJ, McCaffery I, Miller RA. A2AR Antagonism with CPI-444 Induces Antitumor Responses and Augments Efficacy to Anti-PD-(L)1 and Anti-CTLA-4 in Preclinical Models. Cancer Immunol Res. 2018 Oct;6(10):1136-1149. doi: 10.1158/2326-6066.CIR-18-0056. Epub 2018 Aug 21. PMID: 30131376.

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1: Fong L, Hotson A, Powderly JD, Sznol M, Heist RS, Choueiri TK, George S, Hughes BGM, Hellmann MD, Shepard DR, Rini BI, Kummar S, Weise AM, Riese MJ, Markman B, Emens LA, Mahadevan D, Luke JJ, Laport G, Brody JD, Hernandez-Aya L, Bonomi P, Goldman JW, Berim L, Renouf DJ, Goodwin RA, Munneke B, Ho PY, Hsieh J, McCaffery I, Kwei L, Willingham SB, Miller RA. Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer. Cancer Discov. 2020 Jan;10(1):40-53. doi: 10.1158/2159-8290.CD-19-0980. Epub 2019 Nov 15. PMID: 31732494; PMCID: PMC6954326.


2: Iacovelli R, Ciccarese C, Procopio G, Astore S, Cannella MA, Maratta MG, Rizzo M, Verzoni E, Porta C, Tortora G. Current evidence for second-line treatment in metastatic renal cell carcinoma after progression to immune-based combinations. Cancer Treat Rev. 2022 Apr;105:102379. doi: 10.1016/j.ctrv.2022.102379. Epub 2022 Mar 12. PMID: 35303548.


3: Sitkovsky MV. Lessons from the A2A Adenosine Receptor Antagonist-Enabled Tumor Regression and Survival in Patients with Treatment-Refractory Renal Cell Cancer. Cancer Discov. 2020 Jan;10(1):16-19. doi: 10.1158/2159-8290.CD-19-1280. PMID: 31919119.


4: Willingham SB, Ho PY, Hotson A, Hill C, Piccione EC, Hsieh J, Liu L, Buggy JJ, McCaffery I, Miller RA. A2AR Antagonism with CPI-444 Induces Antitumor Responses and Augments Efficacy to Anti-PD-(L)1 and Anti-CTLA-4 in Preclinical Models. Cancer Immunol Res. 2018 Oct;6(10):1136-1149. doi: 10.1158/2326-6066.CIR-18-0056. Epub 2018 Aug 21. PMID: 30131376.

Zhang H, Yu P, Tomar VS, Chen X, Atherton MJ, Lu Z, Zhang HG, Li S, Ortiz A, Gui J, Leu NA, Yan F, Blanco A, Meyer-Ficca ML, Meyer RG, Beiting DP, Li J, Nunez-Cruz S, O'Connor RS, Johnson LR, Minn AJ, George SS, Koumenis C, Diehl JA, Milone MC, Zheng H, Fuchs SY. Targeting PARP11 to avert immunosuppression and improve CAR T therapy in solid tumors. Nat Cancer. 2022 May 30. doi: 10.1038/s43018-022-00383-0. Epub ahead of print. PMID: 35637402.