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Deciphering the tumor suppressor role of P2RX7 receptor and its evaluation as a new drug-target in inflammation-associated carcinogenesis

Having demonstrated that the purinergic P2X7 receptor (P2RX7) tailors the intensity of the inflammatory response in patients with inflammatory bowel diseases (Crohn’s disease), our consortium investigated the therapeutic potential of P2RX7 blockade in mouse models of inflammatory bowel disease and colitis-associated carcinogenesis. We found that both invalidation of P2RX7 gene and treatment with the specific P2RX7 antagonists A438079 and A740003 lowered DSS-induced mucosal inflammation. However, we showed that blockade of P2RX7 functions unexpectedly enhanced tumor formation in vivo. These findings, suggesting that the P2RX7 is essential to support anti-tumor immune responses and/or to restrict neoplastic formation and tumor growth, open up new avenues of research in the field of inflammation and cancer.

We propose within this project done in collaboration with IRCAN, Université de Nice, Dr Valérie Vouret-Craviari; Dr S. Adriouch, Inserm U905, Université de Rouen; Pr Jean Kanellopoulos, INSERM U757 Université Paris Sud, Orsay, to develop new small-molecules P2RX7-specific agonists as new tools to study P2RX7 functions in vivo. We have initiated a “ligand-based” approach to define novel pharmacophore based on extensive computational comparisons of known P2RX7 antagonists with the aim to develop novel antagonistic and agonistic molecules and, possibly, to develop molecule that can dissociate the multiple activities associated with P2RX7 activation (e.g., channel formation and calcium influx vs. larger pore formation). One hundred compounds corresponding to this pharmacophore have been synthesized so far and screened in vitro. Not surprisingly, novel antagonists of human P2RX7, representing very promising “hits” for drugs development (IC50 in the submicromolar range), have been identified during this first round of screening. Unexpectedly and interestingly, the screening phase also led, for the first time, to the identification of novel small-molecule agonists stimulating the activity of P2RX7. This result suggests that agonists and antagonists bind to a same domain within the P2RX7 receptors and those agonists and antagonists adopt a similar pharmacophore.

Interestingly also, preliminary data showed that the agonistic ALIPX02 compound triggers pore formation and passage of large molecules without inducing significant Ca2+ influx, highlighting our capacity to engineer selective molecules that can be used as novel tools to dissociate the multiple activities associated with P2RX7 activation. Before testing these molecules in vivo, we first aim to optimize our molecules based on in silico modeling studies according to ideal ADME parameters. We anticipated that these molecules, and more specifically the agonistic molecules, will represent unique tools to further decipher the anti-tumor role of P2RX7 in vivo and to validate its importance as a new drug-target.