JSH-150

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

JSH-150 (JSH150) 是一种有效的、高选择性的 CDK9 激酶抑制剂，在生化检测中 IC50 为 1 nM，选择性比其他 CDK 激酶家族成员高 300-10000 倍 (CDK7 IC50=1.72 uM)。

JSH-150 (JSH150) is a potent, highly selective inhibitor of CDK9 kinase with IC50 of 1 nM in the biochemical assays, displays 300-10000-fold selectivity over other CDK kinase family members (CDK7 IC50=1.72 uM); also exhibits high selectivity over other 468 kinases/mutants (KINOMEscan S score(1)?=?0.01); displays potent antiproliferative effects against melanoma, neuroblastoma, hepatoma, colon cancer, lung cancer as well as leukemia cell lines, dose-dependently inhibits the phosphorylation of RNA Pol II, suppresses the expression of MCL-1 and c-Myc, arreststhe cell cycle and induces the apoptosis in the leukemia cells; completely suppresses the tumor progression in MV4-11 cell-inoculated xenograft mouse model (10 mg/kg).

The antiproliferative effect of JSH-150 is examined ton a panel of established cancer cell lines. JSH-150 exhibits potent antiproliferative activities in solid tumor cell lines such as A375 (melanoma), A431 (squamous), BE(2)M17 (neuroblastoma), GIST-T1 (GIST) and COLO205 (colon cancer) with GI50 values from 0.002 to 0.044 μM. In the leukemia cell lines including acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and B cell lymphoma cell lines, JSH-150 also displays strong growth inhibition efficacies with GI50s ranging from single to double digit nM. In addition, JSH-150 is much less sensitive in normal CHO cells (GI50: 1.1 μM) compared with the cancer cell lines.

Treatment of JSH-150 at all dosages, i.e., 10, 20 and 30 mg/kg/day, can almost completely suppress the tumor progression in the first two weeks and does not affect the animal’s weight indicating that there is no general cytotoxicity at these doses. After stopping the treatment of JSH-150, the tumors of the animals treated with 10 mpk drug dosage start to grow again. However, this tumor recurrence is not observed in the 20 and 30 mpk dosage groups during the following week after administration of JSH-150 is stopped and p values are quantified on the 21st day, which are 0.042, 0.0035 and 0.0028, respectively. The PK properties of JSH-150 are evaluated in different species including mice, Sprague-Dawley rats and beagle dogs through intravenous injection and oral administration. JSH-150 is absorbed rapidly in dogs and mice (Tmax=1.33 h and 2.00 h respectively) but slowly in rats (Tmax=3.33 h). JSH-150 also displays different half-lives in three different species via oral administration (T1/2=1.55 h in mice, 3.37 h in rats and 20.37 h in dogs), which indicates that it is metabolized very slowly in dogs compared with mice and rats. In addition, JSH-150 exhibits acceptable bioavailability in mice, rats and dogs (F=45.01%, 45.10% and 39.15%, respectively). The PK properties indicated that JSH-150 is suitable for oral administration.

JSH150 | JSH 150

Angiogenesis

CDK

CDK

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2247481-21-4

505.078

C24H33ClN6O2S

>98% (HPLC)

In Vitro:?DMSO : 100 mg/mL (197.99 mM)

COCCNC1CC[C@H](NC2=NC=C(Cl)C(C3=CSC(NCC4(C#N)CCOCC4)=N3)=C2)CC1

4-(((4-(5-Chloro-2-(((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile

(-20℃)

With Ice Pack

≥ 2 years