Abstract 5607: Discovery and preclinical evaluation of a potent, orally bioavailable, highly selective, small molecule PTPN2/1 inhibitor

Abstract Protein tyrosine phosphatase non-receptor type 2 (PTPN2) is ubiquitously expressed, primarily in hematopoietic and placental cells. Critical negative regulator of the JAK-STAT pathway, PTPN2 functions to directly regulate signaling through cytokine receptors, including IFNγ. Thus, enhancing IFNγ sensing and signaling through the inhibition of PTPN2 is a potential therapeutic strategy to improve the efficacy of cancer immunotherapy regimens. Historically, phosphatases are difficult drug targets; due to an intrinsic physicochemical profile of phosphatase inhibitors, finding bioavailable molecules is a great challenge. ZE00-0388 demonstrates sub-nanomolar PTPN2/N1 inhibitory activity and outstanding over 1000-fold selectivity against all other phosphatases. ZE00-0388 demonstrated complete tumor remission in combination with the anti-mPD-1 recombinant mAb therapy in the murine colon adenocarcinoma MC38 in vivo model. ZE00-0388 demonstrates good safety and tolerability; its ADME properties confirm that ZE00-0388 is suitable for further development for combination therapies. Citation Format: Alexei Pushechnikov, Vladislav Parchinsky, Aleksei Riakhovskii, Stepan Mochalov, Ruben Karapetian, Amy Burd, Nikolay Savchuk, Iain Dukes, Ruben Abagyan. Discovery and preclinical evaluation of a potent, orally bioavailable, highly selective, small molecule PTPN2/1 inhibitor [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 5607.