Overcoming high level adenosine-mediated immunosuppression by DZD2269, a potent and selective A2aR antagonist.

ABSTRACT:

Background

Adenosine is a potent immunosuppressant whose levels in the tumor microenvironment (TME) are often much higher than those in normal tissues. Binding of adenosine to its receptor A2aR activates a cascade of genes and leads to immunosuppression. In addition, immune checkpoint blockage markedly increases A2aR expression in T cells, which could dampen their anti-tumor response. Several A2aR antagonists are under clinical development, but with limited clinical benefit reported so far. These A2aR antagonists showed much diminished activity at high adenosine levels found in TME, which may explain their clinical underperformance. We report the discovery and early clinical development of DZD2269, a novel A2aR antagonist which can fully block A2aR mediated immunosuppression common

SUBMITTER: Bai Y 

PROVIDER: S-EPMC9563815 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature