Abstract 519: EVOEXS21546 is a novel non-brain penetrant A2AR inhibitor for cancer immunotherapy with accelerated drug development

Evotec and Exscientia are collaborating to develop an innovative drug discovery platform for accelerating small molecule development in Immuno-Oncology. The primary focus is to target the immunosuppressive adenosine pathway. We have firstly sought to generate a novel and selective, non-brain penetrant A2AR antagonist. EVOEX21546 has been selected as our lead candidate with 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 compound’s effect on other key biological features of T-cell activation including IFN-gamma production and T-cell proliferation. ADME/DMPK data show that EVOEX21546 has a favourable pharmacological profile consistent with its evaluation in syngeneic tumour models. Furthermore, we are pursuing efforts to understand the Mechanism-of-Action of EVOEXS21546 in order to identify the most relevant biomarker of activity for clinical translation. Finally, from the perspective to accelerate the IND submission, EVOEXS21546 entered an INDiGO campaign, an integrated and rapid process to reach IND complemented by high-end integrated CMC. These results, generated in the frame of the A2AR inhibitor pathway, have paved the way to an optimized process for identifying, improving and accelerating the path from drug discovery to the entering into the clinic for Immuno-Oncology drugs. Citation Format: Pierre Fons, Andy Bell, Michael Esquerre, Stephanie Versluys, Florie Bertrand, Iva Hopkins-Navratilova, Sean Robinson, Virgile Visentin, Adrian Schreyer, Richard Cox, Emilie Mirey, Emilie Pelissier, Celia bergeaud, Simone Culurgioni, Jeremy Besnard, Andrew Payne, Jerome Menegotto, Frederic Machet, Celine Poussereau-Pomie, Eric Cogo, Michael Paillasse, Federica Ferigo, Sabrina Pagliarusco, Joanna Lisztwan, Mark Whittaker, Craig Johnstone, Andrew Hopkins. EVOEXS21546 is a novel non-brain penetrant A2AR inhibitor for cancer immunotherapy with accelerated drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 519.