Abstract PR017: Discovery and clinical evaluation of a potent and selective A2A/2B dual receptor antagonist

Abstract

Abstract Elevated adenosine levels present in the tumor microenvironment (TME) produce a net immunosuppressive effect through inhibition of T cell function by two mechanisms of action: Direct T cell effects via A2A receptor agonism and indirect T cell effects via agonism of A2A and A2B receptors on myeloid cells. Our team sought to identify a small molecule dual antagonist of the A2A and A2B receptors with the ability to decrease the immunosuppressive effects of adenosine in the TME and restore anti-tumor immune response. Drawing on our prior experience in the design of A2A receptor antagonists for the potential treatment of Parkinson’s disease, we developed a molecule with sub-nanomolar and single-digit nanomolar affinities for the A2A and A2B receptors respectively and greater than 100-fold selectivity over the related A1 and A3 receptors. A single dose assessment of this molecule in human subjects demonstrated the ability to achieve >99% target engagement (TE) at the A2A receptor and >90% TE at the A2B receptor at trough concentration. This presentation will, for the first time, describe the discovery and early clinical evaluation of this molecule, including disclosure of the structure, human pharmacokinetics, safety, and tolerability. Citation Format: Duane DeMong, Sheila Ranganath, Jared Cumming, Matthew Larsen, Yonglian Zhang, Christopher Plummer, Amjad Ali, Anthony Palmieri, Evan Barry, Pierre Daublain, Pranav Gupta, Manash Chatterjee, Vincent Giranda, Jeremy Presland, Sebastian Schneider, Paul Ciaccio, Daniel Tatosian, Aaron Sather, Ben Turnbull, Steven Silverman, Harry Chobanian, Harini Krishnamurthy, Richard Wnek, Roshi Afshar, Stephen Crowley, Alita Miller, Mark Ayers, Alan Whitehead, Marlene Hinton, Derek Chiang, Robert Orr, Jill Chrencik. Discovery and clinical evaluation of a potent and selective A2A/2B dual receptor antagonist [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR017.