In the present study, we used global proteomics, transcriptomics-based approaches and drug profiling, to identify autophagy/lysosomal pathways as valid therapeutic targets in a subgroup of pediatric ALL.

Highlights •Report a rigorous SAMHD1 chemical probe discovery pipeline •Identified a series of low micromolar SAMHD1 inhibitors, exemplified by TH6342 •TH6342 deterred SAMHD1 dimerization in vitro, a prerequisite for catalysis

The 3D DET3Ct platform can rapidly define potential, clinically relevant data on efficacy of existing drugs in Ovarian Cancer for precision medicine purposes, as well as provide insights on emerging drugs and drug combinations.

TH6342 is a recently reported small molecule inhibitor of SAMHD1. The binding site of TH6342 on SAMHD1 is currently unknown. In the present study we demonstrate that the N-terminal SAM domain of SAMHD1 is not required for inhibition by TH6342.