CRBN-Based Degrader Removes PTP1B and TCPTP to Reawaken Anti-Tumor T Cells
- Scientists converted an F2Pmp-based dual PTP1B/TCPTP inhibitor into a CRBN-recruiting bifunctional degrader, named X1.
- X1 shows improved potency, selectivity, and plasma exposure after intraperitoneal dosing versus earlier tools.
- Degrading both phosphatases boosts TCR signaling in T cells and IFNγ-driven JAK/STAT1 signaling in tumor cells, raising MHC-I antigen presentation.
- In a mouse tumor model, X1 alone or with anti-PD-1 increased T cell infiltration/activation and drove robust anti-tumor efficacy.
💡 Points
F2Pmp warheads are notoriously charged and permeability-poor, so seeing real plasma exposure after IP dosing of a CRBN degrader built on one is the actual win here — event-driven pharmacology bailing out a classically undruggable phosphotyrosine mimetic. Also curious whether ternary-complex formation buys any PTP1B/TCPTP discrimination beyond what the near-identical catalytic sites let the warhead alone achieve.
Discovery and Characterization of a Cereblon-Based Degrader for PTP1B and TCPTP ↗