Masking a bisphosphonate makes acid sphingomyelinase inhibitors cell-active
- The charged amino bisphosphonate inhibitor ARC39 of acid sphingomyelinase was masked to improve cell entry.
- Masked derivatives reached nanomolar activity in cells, about two orders of magnitude better than the parent.
- Cell uptake, stability and related properties were characterized in detail.
💡 Points
Phosphonate masking is a familiar trick, but ASM has lacked a potent cell-active tool, so a hundred-fold gain in cells matters for target validation. Whether the masks unveil cleanly in the lysosome, where ASM works, decides if this is a probe or a lead.
Masked Bisphosphonate Inhibitors of Acid Sphingomyelinase: Improved Cell Penetration and Potency ↗