Hydralazine inhibits cysteamine dioxygenase to treat preeclampsia and senesce glioblastoma

ABSTRACT: Many safe and effective drugs have unknown targets, limiting opportunities to extend their use to other disease states with overlapping etiologies. Here, we have elucidated the mechanism of action of the direct vasodilator, hydralazine (HYZ), which has been used for more than seven decades and remains on the World Health Organization's List of Essential Medicines as a treatment for preeclampsia and hypertensive crisis. Using our chemoproteomic drug de-orphanization approach, we identify a key enzyme mediator of targeted protein degradation, 2-aminoethanethiol dioxygenase (ADO), as a selective HYZ target. The structure of the ADO•HYZ complex shows that the drug chelates the enzyme's metal cofactor in the course of alkylating one of its ligands. The resultant inactivation stabilizes regulators of G-protein signaling (RGS4/5) that are normally marked for degradation by ADO. This activity explains the drug's impact on blood vessel tension, and it comports with prior associations of insufficient RGS levels with both clinical preeclampsia and analogous symptoms in mice. The established importance of ADO in glioblastoma motivated evaluation of the efficacy of HYZ against such cells, revealing that a single dose induces prolonged senescence. The results identify ADO as a novel pharmacological target for both diseases and connect it to a known drug, opening avenues for the rational tailoring of HYZ to create new pharmaceuticals.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Heart, Brain, Cell Culture

SUBMITTER: Kyosuke Shishikura  

LAB HEAD: Megan L. Matthews

PROVIDER: PXD067316 | Pride | 2025-10-24

REPOSITORIES: Pride