In vitro: LDC4297 inhibits CDK7 in vitro in the nano-picomolar range. The affinity of LDC4297 for CDK7 proves to be extremely high. The replication of HCMV in cultured primary human fibroblasts (HFFs) is inhibited by LDC4297 in a concentration-dependent manner with a 50% effective concentration (EC50) value of 24.5 ± 1.3 nM. Notably, CDK7 inhibition by LDC4297 is not associated with general cytotoxicity at submicromolar concentrations. In contrast, LDC4297 induces cytotoxicity in a set of tumor cell lines, i.e., already at extremely low, nanomolar concentrations in specific cases. Anti-HCMV activity of LDC4297 is exerted through a multifaceted mode of action that involves an interference with virus-induced Rb phosphorylation. In vivo: The PK analyses of LDC4297 performed thus far have also been highly promising. An analysis of the PK parameters in CD1 mice reveals positive characteristics after oral administration, as demonstrated for a single-dose treatment (100 mg/kg of LDC4297. The half-life (t1/2z) is determined to be 1.6 h, and a time (Tmax) to a mean peak plasma concentration of 1,297.6 ng/ml is reached 0.5 h after administration, with a continued presence of LDC4297 plasma levels for at least 8 h and a bioavailability of 97.7%.
|Cell lines||human fibroblasts|
|Preparation method||A trypan blue exclusion assay is performed with cultured cells seeded in 24-well plates and incubated with increasing concentrations of antiviral compounds (range, 0.1 to 50 μM) for the durations indicated. Cell staining is achieved with 0.1% trypan blue for 10 min at room temperature before the percentage of viable cells is determined by microscopic counting.|
|Concentrations||0.1 to 50 μM|
|Incubation time||3 days|
|Animal models||CD-1 mice|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||86 mg/mL in DMSO|
A novel CDK7 inhibitor of the Pyrazolotriazine class exerts broad-spectrum antiviral activity at nanomolar concentrations.
Hutterer C, et al. Antimicrob Agents Chemother. 2015 Apr;59(4):2062-71. PMID: 25624324.
Cyclin-dependent kinase 7 controls mRNA synthesis by affecting stability of preinitiation complexes, leading to altered gene expression, cell cycle progression, and survival of tumor cells.
Kelso TW, et al. Mol Cell Biol. 2014 Oct 1;34(19):3675-88. PMID: 25047832.
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Voruciclib (P1446A-05) is a protein kinase inhibitor specific for the cyclin-dependent kinase 4 (CDK4) with IC50s of 90nM, 25nM, and 22nM for CDK4-CyclinD1, CDK1-Cyclin B, and CDK9-Cyclin T, respectively.
CVT-313 is a potent and selective inhibitor of CDK2 that prevents neointimal proliferation, which has an IC50 of 0.5 microM in vitro.
ON123300 is a potent inhibitor of CDK4, with an IC50 of 3.8 nM, with little inhibitory activity against CDKs 1,2,5 and 8.
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