Discovery and Characterization of a Cereblon-Based Degrader for PTP1B and TCPTP

Abstract Protein tyrosine phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP) play non-redundant roles in regulating T cell activation and tumor antigen presentation, making them compelling cancer immunotherapy targets. Recent studies have illustrated the viability of concomitant PTP1B/TCPTP degradation as a promising strategy to drug these proteins. Herein, using a phosphonodifluoromethyl phenylalanine (F2Pmp)-based dual PTP1B and TCPTP inhibitor, we report a cereblon (CRBN)-based small molecule degrader X1 targeting both phosphatases with improved potency, selectivity, and plasma exposure after intraperitoneal administration. X1 enhances T cell receptor (TCR) signaling in T cells and IFNγ-mediated JAK1/2-STAT1 activation in tumor cells, promoting surface MHC-I antigen presentation. X1 alone or combined with anti-PD-1 treatment exhibits robust anti-tumor efficacy in a syngeneic tumor model by increasing T cell infiltration and activation. These findings highlight the translational potential of systemic and concomitant targeting of both PTP1B and TCPTP as a promising strategy for cancer immunotherapy.