CS-2259

中文名称:

CS-2259

中文同义词:

化合物CDKI-73

英文名称:

CDKI-73

英文同义词:

CDKI-73;CS-2259;CDKI-73 (CDKI73);Benzenesulfonamide, 3-[[5-fluoro-4-[4-methyl-2-(methylamino)-5-thiazolyl]-2-pyrimidinyl]amino]-

CAS号:

1421693-22-2

分子式:

C15H15FN6O2S2

分子量:

394.45

EINECS号:

相关类别:

活性分子

Mol文件:

1421693-22-2.mol

沸点 

642.9±65.0 °C(Predicted)

密度 

1.524±0.06 g/cm3(Predicted)

酸度系数(pKa)

10.06±0.60(Predicted)

生物活性

CDKI-73 (LS-007) 是一种有效的 CDK 抑制剂，对CDK1、CDK2、CDK4和CDK9的IC50值分别为8.17 nM，3.27 nM，8.18 nM和5.78 nM。CDKI-73 可诱导癌细胞的凋亡。CDKI-73 是一种口服生物利用型且高效的 CDK9 抑制剂，可用于治疗急性髓细胞性白血病。

靶点

Target Value CDK2 (Cell-free assay) 3.27 nM CDK9 (Cell-free assay) 5.78 nM CDK1 (Cell-free assay) 8.17 nM CDK4 (Cell-free assay) 8.18 nM

Target

Value

CDK2 (Cell-free assay)

3.27 nM

CDK9 (Cell-free assay)

5.78 nM

CDK1 (Cell-free assay)

8.17 nM

CDK4 (Cell-free assay)

8.18 nM

体外研究

CDKI-73 is highly cytotoxic to primary leukemia cells derived from CLL patients (mean LD 50 = 0.08 μM) and shows>500-fold selectivity for primary leukemia cells over normal B-lymphocytes (LD 50 = 40.5 μM). CDKI-73 (0.1 μM, 4 h) inhibits the phosphorylation of serine 2 of RNA polymerase II and MCL1 protein expression in CLL cells. CDKI-73 induced caspase-dependent apoptosis that was preceded by dephosphorylation of cdk9 and serine 2 of RNA polymerase II. CDKI-73 is highly effective against all cell lines tested with an IC 50 in the range of 0.012-0.517 μM; in particular three MLL-AML cell lines, namely MOLM13, MV4-11 and THP-1, were highly sensitive to CDKI-73 with IC 50 values <0.062 μM. Cell Viability Assay. Cell Line: CLL cells. Concentration: 0-1 μM. Incubation Time: 48 h. Result: Shows preferential cytotoxicity in CLL cells.

Cell Line:

CLL cells.

Concentration:

0-1 μM.

Incubation Time:

48 h.

Result:

Shows preferential cytotoxicity in CLL cells.

体内研究

CDKI-73 (25, 50, 100 mg/kg) markedly decreases tumor growth in a dose-dependent manner and results in a prolongation of animal life span (P < 0.001) without causing body weight loss and other overt toxicities.. Animal Model: MV4-11 tumor bearing mice. Dosage: 25 mg/kg. Administration: Orally once everyday for 33 days. Result: Caused a remarkable delay in tumor growth compared to vehicle-treated mice, as reflected in a percentage for the mean tumor volume in treated to control mice of 43% at day 31. Animal Model: Balb/C mice aged 6-8 weeks. Dosage: 2 mg/kg (IV), 10, 20 and 40 mg/kg (PO). (Pharmacokinetic Analysis.) Administration: IV and PO, single dose. Result: The C max increased from 1.29 to 3.66 μM at a mean time of 1 h and the area under the curve (AUC) of CDKI-73 increased from 3.51 to 12.8 μM.h when the oral dose was escalated from 10 to 40 mg/kg. CDKI-73 was eliminated from plasma with a mean terminal half-life (T1/2) of 2 h. Its oral bioavailability (F) ranged from 54 to 85% across the three doses.

Animal Model:

MV4-11 tumor bearing mice.

Dosage:

25 mg/kg.

Administration:

Orally once everyday for 33 days.

Result:

Caused a remarkable delay in tumor growth compared to vehicle-treated mice, as reflected in a percentage for the mean tumor volume in treated to control mice of 43% at day 31.

Animal Model:

Balb/C mice aged 6-8 weeks.

Dosage:

2 mg/kg (IV), 10, 20 and 40 mg/kg (PO). (Pharmacokinetic Analysis.)

Administration:

IV and PO, single dose.

Result:

The C max increased from 1.29 to 3.66 μM at a mean time of 1 h and the area under the curve (AUC) of CDKI-73 increased from 3.51 to 12.8 μM.h when the oral dose was escalated from 10 to 40 mg/kg. CDKI-73 was eliminated from plasma with a mean terminal half-life (T1/2) of 2 h. Its oral bioavailability (F) ranged from 54 to 85% across the three doses.