CPI-444 Chemical Properties

Melting point:

169-171°C

Boiling point:

676.9±65.0 °C(Predicted)

Density 

1.55±0.1 g/cm3(Predicted)

storage temp. 

-20°C

solubility 

Soluble in DMSO (up to at least 25 mg/ml)

form 

solid

pka

4.05±0.30(Predicted)

color 

Beige

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.

CPI-444 Usage And Synthesis

in vivo

Daily treatment of the syngeneic mouse model MC38 with CPI-444 (1, 10, 100 mg/kg) leads to dose-dependent inhibition of tumor growth, leading to tumor elimination in ~30% of treated mice. Combining CPI-444 (100 mg/kg, qd, 14 days) with anti-PD-L1 (200 μg, 3qw, 4 doses) treatment in MC38 models synergistically inhibits tumor growth and eliminates tumors in 90% of treated mice. When cured mice are later re-challenged with MC38 cells, tumor growth is rejected in 100% of challenged mice, indicating that CPI-444 induces systemic anti-tumor immune memory.

Description

CPI-444 (1202402-40-1) is a potent (Ki = 3.54 nM) and selective adenosine A2A receptor antagonist. It blocked the induction of cAMP induced by NECA in HEK-293 cells with an IC50 = 17.03 nM. CPI-444 monotherapy or in combination with anti-PD-1, anti-PD-L1, and anti-CTLA-4 induced T-cell-mediated tumor responses, inhibited tumor growth, and enabled antitumor immune memory. Currently in clinical trials for multiple cancers.

Uses

CPI-444 is an orally administered antagonist to the A2A receptor, and binds to adenosine receptors on the surface of immune cells.

Biological Functions

CPI-444 is a small molecule, oral, checkpoint inhibitor designed to disable a tumor’s ability to subvert attack by the immune system by blocking the binding of adenosine in the tumor microenvironment to the A2A receptor. Adenosine, a metabolite of ATP (adenosine tri-phosphate), is produced within the tumor microenvironment where it may bind to the adenosine A2A receptor present on immune cells and block their activity. CD39 and CD73 are enzymes on the surface of tumor cells and immune cells. These enzymes work in concert to convert ATP to adenosine. In vitro and preclinical studies have shown that dual blockade of CD73 and the A2A receptor may be synergistic.

in vitro

CPI-444 is a potent, oral, selective A2AR antagonist. CD8+ T cell depletion abrogates the efficacy of CPI-444 treatment as a single agent as well as in combination with anti-PD-L1, demonstrating a role for CD8+ T cells in mediating primary and secondary immune responses. Anti-tumor efficacy of CPI-444±anti-PD-L1 is associated with increased CD8+ cell infiltration and activation in MC38 tumor tissues, and a corresponding rise in PD-1 expression on CD8+ T cells in the spleen. Additionally, levels of immune checkpoints are modulated by treatment with CPI-444, including GITR, OX40, and LAG3 on tumor infiltrating lymphocytes and circulating T cells, suggesting a broad role for adenosine mediated immunosuppression.

References

1) Willingham?et al.?(2018),?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.?6?1136 2) Leone?et al.?(2018),?), Inhibition of the adenosine A2a receptor modulates expression of T cell coinhibitory receptors and improves effector function for enhanced checkpoint blockade and ACT in murine cancer models;?Cancer Immunol. Immunother.?671271 3) NCT02655822

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