PYZD-4409 is a selective UBA1 inhibitor with an IC50 of 20 μM. PYZD-4409 induces cell death in malignant cells and is preferentially cytotoxic to malignant cells over normal hematopoietic cells.

Ubiquitin-activating enzyme UBA1:20 μM

PYZD-4409 is preferentially cytotoxic to malignant cells over normal hematopoietic cells. 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. PYZD-4409 (50 μM; 4 hours; K562 leukemia cells) treatment blocks the E1-dependent conjugation of ubiquitin to the E2 enzyme cdc34. PYZD-4409 (0-25 μM; 24 hours; K562 leukemia cells) significantly increases both mRNA and protein levels of Grp78 and Hsp70. 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 an LD50 less than 10 μM in 5 of 8 leukemia and myeloma cell lines. Solid tumor cell lines were less sensitive with an LD50 of approximately 15 to 20 μM [1].

PYZD-4409 (10 mg/kg; intraperitoneal injection; administered every other day for 16 days; male severe combined immunodeficient mice) reduces tumor weight and volume[1].