Plek2 inhibitor NUP-17d is a specific small molecule inhibitor of Pleckstrin-2 (Plek2), binds to Plek2 and Plek2-DEP with high affinity (ITC KD=109 and 350 nM, respectively).
NUP-17d has IC50 of 7.8 µM in the erythroid in vitro proliferation assay.
NUP-17d also significantly inhibited enucleation and differentiation (at higher dosage) of the cultured erythroid cells and induced apoptosis.
NUP-17d is specific for Plek2, showed no inhibitory effect when Plek2 was acutely depleted by shRNA.
NUP-17d dramatically reverted lamellipodia in Plek2 overexpressed cells (Cos-7 cells), blocked Plek2-mediated Akt activation, induceed a confirmation change of Plek2 protein, which leads to Akt dissociation from the lipid-Plek2 complex and instability.
NUP-17d (25 mg/kg, 10% DMSO, 2% ethanol, 2% TWEEN80 and 86% 0.5% captisol) significantly reduced EPO-induced leukocytosis, reticulocytosis, extramedullary erythropoiesis, and vascular occlusions in the lungs of EPO injection models.
NUP-17d (25 mg/kg) reduced myeloproliferation in JAK2V617F models.
NUP-17d (25 mg/kg) demonstrated synergistic effects when combined with Akt inhibitor MK-2206 in human MPN cells.
Pleckstrin-2 (Plek2) is a downstream target of the JAK2-STAT pathway and overexpressed in patients with myeloproliferative neoplasms (MPNs), Plek2 activates Akt and protects Akt through Hsp72.