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 Dmax 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.