Discovery and Evaluation of a PROTAC Degrader Targeting SAMHD1 for the Treatment of Pulmonary Fibrosis

SAMHD1 regulates intracellular nucleotide pool composition, and its overexpression is linked to tumor resistance to nucleoside drugs, organ injury, and fibrosis. Existing SAMHD1 inhibitors only exhibit activity in biochemical assays without intracellular effects, rendering it a difficult-to-drug target. Herein, the discovery of NP12, the first SAMHD1 degrader with intracellular activity was reported. The DC₅₀ value of NP12 for SAMHD1 degradation within 48 h was 1.2 μM, and its degradation efficiency D_max reached 89% at 5 μM. NP12 binds to SAMHD1 in cells and mediates SAMHD1 degradation with low off-target effects. In a bleomycin-induced pulmonary fibrosis mouse model, NP12 delayed pulmonary fibrosis progression and exerted a protective effect on lung tissue. Collectively, PROTAC-mediated SAMHD1 degradation represents an effective strategy for regulating intracellular SAMHD1 activity, and NP12 serves as a novel tool to support studies on SAMHD1 biology and the development of targeted drugs for tumor drug resistance and inflammatory diseases.