Description

Characterization of AB928, an A_2aR antagonist for the treatment of cancer

Walters MJ, Tan JBL, Becker A, Yi F, Leleti MR, Miles D, Jeffery J, Thomas-Tran R, Xu G, Lim WS, Garrido-Shaqfeh S, Jaen JC and Powers JP

Arcus Biosciences, Hayward CA

In the tumor micro-environment, extracellular ATP is sequentially hydrolyzed to adenosine by the ecto-nucleotidases CD39 (ATP→AMP) and CD73 (AMP→adenosine). Adenosine, through activation of the A_2a receptor (A_2aR), is a potent inhibitor of T-cell and NK cell activation, resulting in an immunosuppressed phenotype. Thus, inhibition of A_2aR has recently generated great interest in immuno-oncology. We present the characterization of a novel, selective, and highly potent small molecule antagonist of A_2aR which is slated to enter the clinic in 2017.

The cellular potency of A_2aR antagonists was assessed as a function of decreased cAMP levels in CHO cells stably over-expressing hA_2aR. The ability of AB928 to reverse adenosine-mediated immune suppression of human or mouse CD8⁺ T-cells was determined using CD3/CD28 activation. The pharmacokinetic characteristics of AB928 were assessed in rodent and non-rodent species to facilitate calculation of a projected human dose.

AB928 represents a novel series of potent and selective compounds designed to inhibit adenosine-mediated A_2aR activation. This molecule is different from most known A_2aR antagonists in that it does not possess any CNS-mediated pharmacology. AB928 inhibited NECA-mediated A_2aR activation with single-digit nM potency. AB928 did not significantly inhibit any of the major CYP450 isozymes and did not significantly block the potassium ion channel hERG. AB928 significantly reversed the ability of adenosine to suppress CD8⁺ T cell activation as indicated by increased levels of cytokines. AB928 also inhibited mouse A_2aR. Pharmacokinetic characterization of AB928 showed it to be orally bioavailable with characteristics suitable for human dosing that will allow ≥ 90% target inhibition over 24 hrs.

AB928 is a potent, selective and peripherally restricted antagonist of the A_2aR receptor which is slated to enter clinical development in 2017.