Discovery of Novel Alkynylbenzene Scaffold-Based PTPN2-Selective Degrader PD-305 with Exceptional Potency and In Vivo...

Targeted degradation of PTPN2 is an attractive cancer immunotherapy strategy. However, unfavorable physicochemical properties limit the development of current PTPN2 degraders. In this study, using a ring-opening scaffold-hopping strategy, we identified a class of alkyne-containing PTPN2 ligands, which were subsequently employed for PROTAC design. Through optimizing linkers and CRBN ligands, we obtained PD-305, featuring a rigid linker and a naphtholactam-based ligand. PD-305 exhibits subnanomolar degradation potency (DC₅₀ = 0.25 nM, 868-fold superior to the previously discovered PVD-06) and good subtype selectivity (PTPN2/PTPN1 selectivity >20-fold). Compared to previous PTPN2 degraders, it displays lower molecular weight, fewer hydrogen bond donors/acceptors, and a reduced cLogP. PD-305 exhibited nanomolar antiproliferation potency in the IFN-γ stimulated HT-29 cell line, nearly 80-fold more potent than the clinical candidate AC484. Moreover, it possessed excellent in vivo PTPN2 degradation potency and effectively suppressed tumor growth in mice. Collectively, PD-305 is a promising lead compound worthy of further study.