PYZD-4409

PYZD-4409 is a specific inhibitor of the ubiquitin-activating enzyme UBA1 with an IC₅₀ of 20 μM (cell-free enzymatic assay). PYZD-4409 induces cell death in malignant cells and preferentially inhibits the clonogenic growth of primary acute myeloid leukemia cells^[1]. IC50 & Target:IC50: 20 μM (ubiquitin-activating enzyme UBA1)^[1] In Vitro: PYZD-4409 (10-40 μM; 72 hours; myeloma, leukemia, and solid tumor cell lines, primary AML cells and normal hematopoietic cells) induces cell death with a LD₅₀ less than 10 μM in 5 of 8 leukemia and myeloma cell lines. In contrast, solid tumor cell lines were less sensitive with an LD₅₀ of approximately 15 to 20 μM. PYZD-4409 is preferentially cytotoxic to malignant cells over normal hematopoietic cells^[1].
PYZD-4409 (50 μM; 4 hours; K562 leukemia cells) treatment blocks the E1-dependent conjugation of ubiquitin to the E2 enzyme cdc34^[1].
PYZD-4409 (0-25 μM; 24 hours; K562 leukemia cells) significantly increases both mRNA and protein levels of Grp78 and Hsp70. In addition, PYZD-4409 increases levels of phospho-JNK and phospho-p38 mitogen-activated protein kinase, which have also been linked to ER stress and the unfolded protein response^[1]. In Vivo: PYZD-4409 (10 mg/kg; intraperitoneal injection; daily on alternate days; for 16 days; male severe combined immunodeficient mice) decreases tumor weight and volume without untoward toxicity^[1].