Summary
A bioRxiv preprint reports that KPB82 selectively inhibits ACER2 and reduces doxorubicin-induced cytotoxicity in several cell models, including tumor-derived cells. The findings are from laboratory experiments, not studies in animals or patients.
A bioRxiv preprint posted on October 2, 2026, reports that KPB82 is a potent, selective inhibitor of alkaline ceramidase 2 (ACER2). In cell experiments, the compound also reduced cytotoxicity caused by doxorubicin in several tumor-derived cell models and in primary human umbilical vein endothelial cells. The result makes KPB82 a potential tool for studying ACER2, while showing that inhibiting the enzyme can protect cells from doxorubicin under the conditions tested.
KPB82 selectively inhibits ACER2
ACER2 is an enzyme that breaks down ceramides into sphingosine and free fatty acids. The researchers report that KPB82 inhibited ACER2 in in-vitro enzyme assays, with an IC50 of 190 nM. An IC50 is the concentration that produces half-maximal inhibition in a given assay. KPB82 showed minimal activity against acid and neutral ceramidases, with IC50 values above 100 µM, and no significant inhibition of the related enzymes alkaline ceramidase 1 and 3. Kinetic experiments indicated that KPB82 competes with ACER2’s substrate.
To examine how the compound might bind, the team used an ACER2 structure model generated with AlphaFold3 and performed molecular docking. The computational analysis placed KPB82 in a predicted substrate-binding pocket, with proposed interactions involving Asp93 and His215. These results offer a model for its binding; they are distinct from an experimentally determined structure of the inhibitor bound to ACER2.
Cell experiments reveal protection from doxorubicin
The researchers used lactate dehydrogenase release assays to assess cell damage. They report that KPB82 reduced doxorubicin-induced cytotoxicity in HeLa cells engineered to overexpress ACER2, as well as in HCT116 and RT4 cells and primary human umbilical vein endothelial cells. Lipidomic analysis also showed lower sphingosine production when ACER2 was overexpressed or cells were treated with doxorubicin in the presence of KPB82.
The protection of tumor-derived cells is an important part of the finding: it means the enzyme inhibitor did not simply make those cells more vulnerable to doxorubicin in these experiments. The authors present KPB82 as a tool for investigating ceramide metabolism and ACER2-related signalling. Any implications for cancer treatment remain a separate question, since the reported evidence comes from cell experiments in a preprint, not studies of treatment outcomes in animals or people.