Design, Synthesis, and Bioevaluation of 2-Aminopteridin-7(8H)-one Derivatives as Novel Potent Adenosine A_2A Receptor Antagonists for Cancer Immunotherapy

Abstract

In recent years, the adenosine A2A receptor (A2AR) has shown exciting progress in the development of immunotherapies for the treatment of cancer. Herein, a 2-amino-7,9-dihydro-8H-purin-8-one compound (1) was identified as an A2AR antagonist hit through in-house library screening. Extensive structure–activity relationship (SAR) studies led to the discovery of 2-aminopteridin-7­(8H)-one derivatives, which showed high potencies on A2AR in the cAMP assay. Compound 57 stood out with an IC50 value of 8.3 ± 0.4 nM against A2AR at the 5′-N-ethylcarboxamidoadenosine (NECA) level of 40 nM. The antagonistic effect of 57 was sustained even at a higher NECA concentration of 1 μM, which mimicked the adenosine level in the tumor microenvironment (TME). Importantly, 57 enhanced T cell activation in both the IL-2 production assay and the cancer-cell-killing model, thus demonstrating its potential as a lead for developing novel A2AR antagonists in cancer immunotherapy.

Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer

“…The engagement of PD-L1 and PD-1 exerts inhibitory effects on T cells by inducing their apoptosis and anergy ( 36 ). To investigate whether TSM-1 could reverse the negative influence executed by cancer cells on T cells, we constructed a coculture model of tumor cells with activated Jurkat cells in vitro ( 37 ). IL-2, a signature cytokine of activated T cells, was used as a biomarker for monitoring T cell activation and proliferation.…”

The Role of Microglial Purinergic Receptors in Pain Signaling

“…Therefore, the current evidence supports dual, opposing roles of A 2A receptors—as pronociceptive modulators and anti-inflammatory regulators—in the central nervous system (CNS) glial cells. Some allosteric modulators of A 2A receptors have been identified and studied concerning inflammatory regulation [ 30 , 31 ]. Future studies establishing the physiologic functions of A 2A receptors are awaited.…”

Discovery of Pyridinone Derivatives as Potent, Selective, and Orally Bioavailable Adenosine A2A Receptor Antagonists for Cancer Immunotherapy

“…21 We previously reported 2-aminopteridin-7(8H)-one derivatives as potent adenosine A 2A R antagonists, which kept good activity at the TME-mimicking high NECA concentration of 1 μM. 23 However, the pharmacokinetic (PK) profiles of the pteridinone compounds were unsatisfactory. In this work, we identified a pyridinone compound 1 as a hit of A 2A R antagonist (35.3% inhibition against A 2A R @ 10 μM) through our inhouse compound library screening with the GloSensor cAMP Chemistry.…”

“…We previously reported 2-aminopteridin-7­(8 H )-one derivatives as potent adenosine A 2A R antagonists, which kept good activity at the TME-mimicking high NECA concentration of 1 μM . However, the pharmacokinetic (PK) profiles of the pteridinone compounds were unsatisfactory.…”