Abstract PR001: Discovery of Etrumadenant, a first-in-class dual A2a and A2b adenosine receptor antagonist for cancer immunotherapy
Authors: Sharif Ehesan U. , Miles Dillon H. , Rosen Brandon R. , Beatty Joel , Jeffrey Jenna L. , Debien Laurent P. P. , Thomas-Tran Rhiannon , Mandal Debashis , Direnzo Dan , Marubayashi Sachie , Zhang Kristen , Soriano Ferdie , Ginn Elaine , Soni Divyank , Chen Pei-Yu , Jin Lixia , Young Steve W. , Walters Matt J. , Leleti Manmohan R. , Powers Jay P. 
Published: December 2024

Abstract
High levels of adenosine are generated in the tumor microenvironment (TME) by sequential hydrolysis of extracellular ATP by the ecto-nucleotidases CD39 (ATP→AMP) and CD73 (AMP→adenosine). Adenosine activates A2a and A2b adenosine receptors on immune cells, resulting in immunosuppression. Since A2aR is expressed by a variety of lymphocytes, the suppressive effects of adenosine on this cell type can be potentially reversed by blocking the A2aR. In contrast, myeloid cells that have comparable expression of A2aR and A2bR require dual A2a/bR blockade for full reversal of the immunosuppressive effects of adenosine. The first generation of adenosine antagonists deployed in oncology were repurposed CNS drug candidates with properties that were deemed less than optimal for anti-tumor efficacy (e.g., A2aR-selective, good BBB permeability, not optimized for minimal plasma protein binding, etc.). We sought to design a potent and selective dual antagonist of A2aR and A2bR to effectively block the high concentrations of adenosine found in tumors, with diminished brain penetration, and minimal non-specific binding to plasma proteins. Using a pharmacophore mapping approach, we discovered potent A2aR antagonists with favorable PK profile in rats, good selectivity, and moderate potency against A2bR. Systematic SAR studies led to improvement in A2bR potency, which ultimately resulted in Etrumadenant (AB928). Etrumadenant inhibits both A2aR and A2bR with similar potencies (KB: 1.4 nM and 2 nM, respectively), and is highly selective against other targets in the adenosine pathway with minimal penetration across the blood brain barrier. Etrumadenant provides superior dendritic cell activity compared to A2aR antagonist alone. Its combination with immunogenic chemotherapy enhances immune activity and suppresses tumor growth and metastasis in vivo. These data support our rational design of a dual A2a and A2b adenosine receptor antagonist to impact adenosine biology on multiple cell types within the TME. Etrumadenant is currently undergoing phase 2 clinical trials in colorectal and lung cancer patients.
Citation Format: Ehesan U. Sharif, Dillon H. Miles, Brandon R. Rosen, Joel Beatty, Jenna L. Jeffrey, Laurent P. P. Debien, Rhiannon Thomas-Tran, Debashis Mandal, Dan Direnzo, Sachie Marubayashi, Kristen Zhang, Ferdie Soriano, Elaine Ginn, Divyank Soni, Pei-Yu Chen, Lixia Jin, Steve W. Young, Matt J. Walters, Manmohan R. Leleti, Jay P. Powers. Discovery of Etrumadenant, a first-in-class dual A2a and A2b adenosine receptor antagonist for cancer immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr PR001