KPB82, a ceramide-mimetic sulfonamide, is a selective ACER2 inhibitor in a bioRxiv preprint
- ACER2 hydrolyses ceramides to sphingosine and fatty acids, and no pharmacological tool for it existed.
- KPB82, a dodecane sulfonamide carrying a ceramide-like hydroxyphenylpropyl group, inhibited ACER2 potently, with minimal activity on acid and neutral ceramidases and none on ACER1 or ACER3.
- Kinetics were competitive, and docking into an AlphaFold3 model placed it in the substrate pocket near the Zn2+-binding histidines.
- The title reports protection of tumor and primary cells from doxorubicin cytotoxicity.
💡 Points
No ACER2 tool compound until now, so a competitive, ACER1/ACER3-sparing hit matters. A dodecane sulfonamide with a hydroxyphenylpropyl headgroup reads like a ceramide mimic, and the docked pose near the Zn2+ histidines is only an AlphaFold3 hypothesis. I'd want IC50s, an SAR series, and cellular target engagement before trusting the doxorubicin rescue.