Abstract 3768: Identification of a novel non-brain penetrant A2AR inhibitor and proof-of-concept of CD73 and A2AR/CD73 small-molecule inhibitors for cancer immunotherapy
Authors: Pierre Fons, Andy Bell, Michael Esquerre, Stephanie Versluys, Florie Bertrand, Celine Poussereau-Pomie, Adrian Schreyer, Richard Cox, Jeremy Besnard, Michael Paillasse, Mark Swindells, Joanna Lisztwan, Craig Johnstone, Mark Whittaker, Andrew Hopkins
Journal: Cancer Research (2018)

Abstract Adenosine, generated by CD73 is a key driver of immunosuppression in the hypoxic tumour microenvironment (TME). In immune-inflamed tumours, with CD8+ T-cell infiltrates, adenosine signalling is a cause of resistance to immune checkpoint therapies (ICTs) through the inhibition of T-cells, NK cells and more largely of the overall antitumor immunity. Evotec and Exscientia are collaborating to develop a drug discovery platform for accelerating small molecule development in Immuno-Oncology targeting this adenosine pathway. The platform has integrated a unique biophysical screening approach to the adenosine receptors and CD73 to drive automated medicinal chemistry design with a translational-focused screening cascade. We have firstly sought to generate a novel non-brain penetrant A2AR antagonist. We have selected EVOEX21546 as our lead candidate and demonstrated its in vitro potency on primary human CD3+ T lymphocytes for inducing the recovery of IL-2 production after CADO-mediated inhibition of T-cell activation. In addition, we have demonstrated the compounds effect on other key biological features of T-cell activation including IFN-γ production and T-cell proliferation. ADME/DMPK data show that EVOEX21546 has a favourable pharmacological profile consistent with its evaluation in in vivo models resistant to ICTs before its entry into preclinical development. In parallel of this first drug discovery program, we have initiated research of CD73 specific inhibitory molecules and two series binding at orthogonal sites on CD73 have been identified. In vitro functional potency has been demonstrated for the CD73 inhibitors for inducing recovery of AMP-induced inhibition of T-cells activation as measured through IL-2 production. The series are under optimization to improve activity, solubility and ADME/DMPK parameters. Finally, from the perspective of developing dual pharmacological profile for A2AR and CD73 inhibition, we have assessed in a primary human CD3+ T-lymphocyte assay the synergy between the two targets in order to optimize the recovery of T-cell activation. Fragment screening has been performed for this approach to further aid design new molecules with a dual pharmacological profile. These results, have paved the way to an optimized process for identifying, improving and accelerating drug discovery in Immuno-Oncology in the frame of the adenosinergic immunosuppressive pathway. Citation Format: Pierre Fons, Andy Bell, Michael Esquerre, Stephanie Versluys, Florie Bertrand, Celine Poussereau-Pomie, Adrian Schreyer, Richard Cox, Jeremy Besnard, Michael Paillasse, Mark Swindells, Joanna Lisztwan, Craig Johnstone, Mark Whittaker, Andrew Hopkins. Identification of a novel non-brain penetrant A2AR inhibitor and proof-of-concept of CD73 and A2AR/CD73 small-molecule inhibitors for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3768.