Project

Current immune-oncology treatments primarily rely on costly monoclonal antibodies and exhibit success rates around 50%. Consequently,

there is increasing biopharmaceutical interest to develop small-molecules targeting the immune metabolism that complement existing

immune-oncology therapies. This project addresses the characterization and therapeutic intervention of the A2B adenosine receptor (AR),

a G-protein-coupled receptor (GPCR) which is part of the purinergic signaling pathway commonly altered in various tumors. As compared

to A2AAR antagonists in clinical trials, blocking the A2BAR is a selective mechanism of therapeutic intervention, since this receptor is

silent under physiological conditions. We will identify and optimize high affinity small-molecule antagonists for the A2BAR, and evolve

these within a multitarget strategy that considers the related A2AAR, CD73 and the P2Y1 GPCR, to deliver dual inhibitors of the purinergic

signaling system. This strategy builds up on our recently published data and promising compounds in clinical trials, showing dual A2A/A2B

dual affinity. The selective A2BAR antagonists developed along the project, on the other hand, will guide the design novel agonist

scaffolds, and both types of molecules will be used to characterize the role of this receptor in the tumor microenvironment. Our ligand

design will benefit from the recent experimental structure of active A2BAR, which we plan to supplement with new experimental structures

of inactive A2BAR with our antagonists. Finally, the characterization of the A2BAR as immune-oncology target will be complemented with the exploration of the mechanism of cancer-related somatic mutations described for this receptor, using a

methodology that we envision as generic for similar GPCR-pathogenic mutations that alter the receptors conformational equilibrium. The

proposal builds upon the expertise of the PI in GPCR structure-based approaches, reinforced by our recently developed original

representation of receptor equilibrium solved by free energy perturbation simulations. In combination with chemistry, immuno-oncology and

structural biology experiments, our interdisciplinary project will widen the field of immune-oncology therapies with small molecules.