423148-78-1

生物活性靶点体外研究体内研究 423148-78-1 试剂级价格

423148-78-1

CAS号:423148-78-1
英文名:(E)-1-(3-chloro-4-fluorophenyl)-4-((5-nitrofuran-2-yl)Methylene)pyrazolidine-3,5-dione
中文名:423148-78-1
CBNumber:CB82609290
分子式:C14H7ClFN3O5
分子量:351.67
MOL File:423148-78-1.mol

423148-78-1化学性质

密度 :1.662±0.06 g/cm3(Predicted)
储存条件 :Store at -20°C
溶解度 :Soluble in DMSO
形态 :solid
酸度系数(pKa) :7.12±0.20(Predicted)
颜色 :Brown

423148-78-1性质、用途与生产工艺

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.

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.