T cell protein tyrosine phosphatase (TCPTP) is a non-receptor type protein tyrosine phosphatase (PTP). Phosphorylation-based signaling mediated by PTPs plays vital roles in regulating cell growth, differentiation, survival, and migration. Recently, TCPTP was identified as a cancer immunotherapy target by in vivo loss of function genetic screen. TCPTP deletion in B16 melanoma murine tumor cells significantly enhances IFN-γ signaling and promotes tumor cell antigen presentation, while the loss of TCPTP in T cells enhances TCR signaling and stimulates cell proliferation and activation. These observations suggest that global inhibition of TCPTP may improve the efficacy of cancer immunotherapy regimens by altering tumor cells and T cells synergistically. Thus, the development of novel and effective strategies for TCPTP inhibition is highly desirable. Through rational design and systematic screening, we discovered a potent TCPTP PROTAC degrader TP1L that selectively induces degradation of TCPTP in multiple cell lines with low nanomolar DC50s. As expected, treatment of TP1L increases the phosphorylation level of reported TCPTP substrates such as pSTAT1, pJAK1, and pJAK3. TP1L intensifies cellular IFN-γ signaling in B16 murine tumor cells and raises MHC-I expression level. Furthermore, TP1L effectively and selectively induces TCPTP degradation in vivo. In summary, our work provides a novel approach to target TCPTP for the development of cancer immunotherapy and a chemical tool for the in-depth investigation of the TCPTP's functions.

Discovery of a first-in-class potent and selective TCPTP degrader

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