ZT-1a (STK39 inhibitor ZT-1a, SPAK-IN-ZT-1a) is a novel potent, selective SPAK kinase (STK39) inhibitor.
ZT-1a potently inhibited SLC12A cation-Cl-cotransporters (CCC), phosphorylation of NKCC1 p-Thr203/207/212 by 72% at 1uM and phosphorylation of KCC sites 1/2 by 65-77% at 3 uM in HEK-293 cells.
ZT-1a is a more potent modulator of SPAK-dependent CCC phosphorylation than the current SPAK kinase inhibitors Closantel, STOCK1S-50699, and STOCK1S-14279.
ZT-1a inhibited SPAK phosphorylation at Ser373 in HEK-293 cells (70% inhibition at 3-10 uM).
ZT-1a disrupts SPAK interaction with WNK but not with MO25α, reduces SPAK-dependent CCC phosphorylation in cells, inhibits NKCC1 but stimulates KCC3 activity.
ZT-1a decreases SPAK-CCC phosphorylation in hemorrhagic hydrocephalus, modulates primary cortical neuron volume, reduces stroke-associated cerebral edema and infarct, improves neurological function after ischemic stroke in vivo.