PYZD-4409

PYZD-4409 is a **novel small molecule inhibitor** of the **ubiquitin-activating enzyme E1** (also known as UBA1), with an IC50 of 20 μM in cell-free enzymatic assays. It was developed as a pyrazolidine-based pharmacophore. The drug preferentially induces cell death in malignant hematologic cells, including acute myeloid leukemia (AML) and multiple myeloma, showing cytotoxicity in leukemia, myeloma, and several solid tumor cell lines. It operates by inhibiting the activation of ubiquitin and its subsequent transfer to the E2 enzyme, thereby blocking proteasome-dependent protein degradation, leading to accumulation of short-lived proteins such as p53 and cyclin D3, and triggering ER stress and apoptosis. PYZD-4409 showed antitumor activity in mouse models of leukemia and selectively inhibited clonogenic growth of AML cells over normal hematopoietic cells[1][3][5].

Other names

(4E)-1-(3-chloro-4-fluorophenyl)-4-[(5-nitrofuran-2-yl)methylidene]pyrazolidine-3,5-dione