Abstract 5609: A novel PTPN1/2 inhibitor with high oral bioavailability enhances the antitumoral response

Abstract PTPN1/2 phosphatases are major negative regulators of the antitumor immune response. Inhibiting or depleting PTPN1/2 sensitizes cancer and immune cells to interferon gamma (IFNγ), reshapes the tumor microenvironment and triggers a coordinated antitumor immune response involving myeloid cells, NK, T cells, and cancer cells. Although protein phosphatases were long considered undruggable due to their highly polar catalytic pocket, several small molecule inhibitors of PTPN1/2 have recently been discovered. Most of these inhibitors mimic the phosphate of the natural substrate by the 1, 2, 5-thiadiazolidin-3-one 1, 1-dioxide (TDZ) moiety. Although incorporating a TDZ ensures potency while overcoming the instability of the phosphate group, the resulting inhibitors are very polar. As a consequence, most of the TDZ-containing inhibitors suffer from low oral bioavailability. Nevertheless, 2 small molecules have entered clinical trials. We have discovered a small molecule inhibitor of PTPN1/2 with high specificity and human potency comparable to known PTPN1/2 inhibitors. This novel small molecule displays high exposure in preclinical species, due to its high oral bioavailability. To assess the human and mouse cellular potency of our compound, we measured pSTAT1 in cancer cells upon IFNγ treatment and we observed large discrepancies between human and mouse potency for most PTPN1/2 inhibitors. Whereas previously described PTPN1/2 inhibitors show much higher potency in mouse compared to human cells, our novel compound displays higher potency in human compared to mouse cells. Upon in vivo dosing, our PTPN1/2 inhibitor showed efficacy in a syngeneic model, resulting in tumor growth inhibition, target engagement and pharmacodynamic readout. To further determine efficacy in human cells, we tested our compound on human cancer and immune cells, as well as on Patient Derived Tumor Fragments (PDTFs), an innovative ex vivo technique proven to be highly predictive of patient clinical responsiveness to immunotherapy. In this system, drugs are directly applied to slices of fresh human tumors and treatment-induced changes (e.g. cytokines levels) are measured. In both in vitro assays and PDTFs, our PTPN1/2 inhibitor showed signs consistent with a robust anti-tumor response in line with the expected mechanism of action, creating confidence that the molecules will engage the immune system in human patients. Overall, this is the first report of a specific PTPN1/2 inhibitor with competitive human potency and high bioavailability, making it an ideal candidate for clinical development. Citation Format: Angélique Pabois, Alessandra Lopes, Clément Bonnel, João Marchante, Theodore J. Sanders, Michael Deligny, Alexis Goffaux, Wilfried Cathou, Aurore Smets, Inês Amendoeira Cabral, Marie-Claire Letellier, Bérénice Lossignol, Géraldine Genard, Aura Condila, Céline Dotreppe, Margreet Brouwer, Annelise Hermant, Catherine Hoofd, Reece Marillier, Yvonne McGrath, Steven Van der Plas, Silvia Pandolfi. A novel PTPN1/2 inhibitor with high oral bioavailability enhances the antitumoral response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5609.