PYZD-4409

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

PYZD-4409 是泛素激活酶 (E1) 的特异性抑制剂，IC50 为 20 uM。

PYZD-4409 is a specific inhibitor of ubiquitin-activating enzyme (E1) with IC50 of 20 uM, inhibits the ATP-dependent activation of ubiquitin and subsequent transfer of the activated ubiquitin from the E1 to the common human E2 enzyme UBE2E2; blockes the E1-dependent conjugation of ubiquitin to the E2 enzyme cdc3, induces cell death in hematologic malignant cell lines and primary patient samples preferentially over normal hematopoietic cells; decreases tumor weight and volume without untoward toxicity in vivo.

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.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. 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. Cell Cytotoxicity AssayCell Line:Myeloma, leukemia, and solid tumor cell lines, primary AML cells and normal hematopoietic cellsConcentration:10 μM, 20 μM, 30 μM, 40 μMIncubation Time:72 hours Result:Induced 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.Western Blot Analysis Cell Line:K562 leukemia cells Concentration:50 μM Incubation Time:4 hours Result:Blocked the E1-dependent conjugation of ubiquitin to the E2 enzyme cdc34.RT-PCR Cell Line:K562 cells Concentration:0 μM, 10 μM, 25 μM Incubation Time:24 hours Result:Significantly increased both mRNA and protein levels of Grp78 and Hsp70.

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. Animal Model:Male severe combined immunodeficient (SCID) mice with MDAY-D2 murine leukemia cells Dosage:10 mg/kg Administration:Intraperitoneal injection; daily on alternate days; for 16 days Result:Delayed tumor growth and decreased tumor weight without untoward toxicity.

PYZD4409 | PYZD 4409

Proteasome/Ubiquitin

E1

E1

Cancer

——

423148-78-1

351.67

C14H7ClFN3O5

>98% (HPLC)

DMSO: ≥ 35 mg/mL

O=C(/C1=C/C2=CC=C([N+]([O-])=O)O2)NN(C3=CC=C(F)C(Cl)=C3)C1=O

3,5-Pyrazolidinedione, 1-(3-chloro-4-fluorophenyl)-4-[(5-nitro-2-furanyl)methylene]-

(-20℃)

With Ice Pack

≥ 2 years