Clinical efficacy of anti PD-1/PD-L1 immunotherapy is greatly limited by upregulation of PD-1 signaling and mediators of PD-1 signaling are emerging as attractive targets to sensitize tumor cells to immunotherapy. The protein tyrosine phosphatase nonreceptor type 2 (PTPN2) and its close superfamily member, PTPN1 (also known as PTP1B), are such modulators of immune oncology that have been shown to promote tumorigenesis by attenuating tumor-directed immunity [1,2]. PTPN2 deletion was first identified to enhance the response of B16 melanoma cells to anti-PD-1 immunotherapy in a CRISPR-Cas9 screen [3]. The PTPN2-null B16 cells had enhanced antigen presentation and increased susceptibility to cytotoxic CD8+ T cells, and PTPN2-null tumors showed enhanced CD8+ infiltration and impaired growth in response to IFN-γ stimulation [3]. Shortly after it was shown that PTPN2 is a negative regulator of JAK/STAT signaling and given that JAK/STAT signaling downstream of the IFN-γ receptor induces PD-L1 expression on tumor cells and is critical to the response to anti-PD-1 cancer therapy, inhibiting PTPN2 predictably increased responses to anti-PD-L1 therapy in murine melanoma YUMM1.1 cells in vitro and in vivo [4]. Furthermore, PTPN2 was identified as a candidate regulator of the CD8+ T cell response in a pooled in vivo loss-of-function screen [5], and inhibition of PTPN2 was demonstrated to sensitize B16 melanoma cells to anti-PD-1 [6]. Recent findings also showed that aberrant PTPN2 activation may contribute to triple-negative breast cancer [7] and acute myeloid leukemia [8]. As for PTPN1, its enhanced expression is reported to restrict T-cell expansion and cytotoxicity, thereby promoting tumor growth [2]. Deletion of T cell-specific PTPN1 augments STAT5 signaling, leading to heightened antigen-induced expansion and cytotoxicity of CD8+ T cells, ultimately suppressing tumor growth. Taken together, these observations have established PTPN2/PTPN1 inhibition as an attractive strategy to sensitize tumor cells to anticancer immunotherapy [9].

The development of clinically applicable phosphatase inhibitors has been slowed down by the challenges such as unfavorable pharmacokinetics due to the highly cationic phosphatase active site and the relative shallow nature of the protein surface. A significant milestone in phosphatase inhibitor development has been reached by the structure-based design of related five-membered heterocyclic phosphor-tyrosine mimetics, such as 1,2,5-thiadiazolidin-3-one 1,1-dioxide (TDZ), or the isothiazolidin-3(2H)-one 1,1-dioxide (IZD) [10], which are proved to retain the key binding interaction with enhanced membrane permeability. The motifs have been successfully utilized in the design of inhibitors targeting PTPN2 and PTPN1 (Fig. 1), which share a high degree of catalytic domain sequence and structural identity [11,12]. Two orally bioavailable small molecule PTPN2/N1 inhibitors, ABBV-CLS-484 (NCT04777994) and ABBV-CLS-579 (NCT04417465, structure not disclosed), have entered clinical trials after demonstrating promising preclinical results [11,12], and compound-182 was developed as an ABBV-CLS-484 derivative [13]. Based on the thiadiazolidinone dioxide scaffold, the development of PTPN2 degraders were also described [14,15]. Here we report a structure-activity exploration of ABBV-CLS-484 that resulted in the identification of the phosphor-tyrosine mimetic 4 as a novel PTPN2/N1 small molecule inhibitor with nanomolar potency and improved oral bioavailability across different species.