423148-78-1

中文名称:

423148-78-1

中文同义词:

泛素激活酶E1抑制剂(PYZD-4409)

英文名称:

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

英文同义词:

(E)-1-(3-chloro-4-fluorophenyl)-4-((5-nitrofuran-2-yl)Methylene)pyrazolidine-3,5-dione;PYZD 4409;(E)-1-(3-chloro-4-fluorophenyl)-4-((5-nitrofuran-2-yl)Methylene)pyrazolidine-3,5-dione 3,5-Pyrazolidinedione, 1-(3-chloro-4-fluorophenyl)-4-[(5-nitro-2-furanyl)methylene]-;PYZD4409;PYZD 4409;1-(3-Chloro-4-fluorophenyl)-4-[(5-nitro-2-furanyl)methylene]-3,5-pyrazolidinedione;3,5-Pyrazolidinedione, 1-(3-chloro-4-fluorophenyl)-4-[(5-nitro-2-furanyl)methylene]-;PYZD-4409 >=98% (HPLC)

CAS号:

423148-78-1

分子式:

C14H7ClFN3O5

分子量:

351.67

EINECS号:

相关类别:

细胞生物学试剂

Mol文件:

423148-78-1.mol

密度 

1.662±0.06 g/cm3(Predicted)

酸度系数(pKa)

7.12±0.20(Predicted)

生物活性

PYZD-4409 是 ubiquitin-activating enzyme UBA1 的特异性抑制剂，其 IC50 值为 20 μM。PYZD-4409 能诱导恶性细胞死亡，并优先抑制原发性急性髓性白血病细胞的生长。

靶点

IC50: 20 μM (ubiquitin-activating enzyme UBA1)

体外研究

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 LD 50 less than 10 μM in 5 of 8 leukemia and myeloma cell lines. In contrast, solid tumor cell lines were less sensitive with an LD 50 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 Assay Cell Line: Myeloma, leukemia, and solid tumor cell lines, primary AML cells and normal hematopoietic cells Concentration: 10 μM, 20 μM, 30 μM, 40 μM Incubation Time: 72 hours Result: Induced cell death with a LD 50 less than 10 μM in 5 of 8 leukemia and myeloma cell lines. In contrast, solid tumor cell lines were less sensitive with an LD 50 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.

Cell Line:

Myeloma, leukemia, and solid tumor cell lines, primary AML cells and normal hematopoietic cells

Concentration:

10 μM, 20 μM, 30 μM, 40 μM

Incubation Time:

72 hours

Result:

Induced cell death with a LD 50 less than 10 μM in 5 of 8 leukemia and myeloma cell lines. In contrast, solid tumor cell lines were less sensitive with an LD 50 of approximately 15 to 20 μM.

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.

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.

体内研究

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.

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.