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
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
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
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
74.3 |
182.24 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
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.
| 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.
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.
