Bicyclic pyridine compositions and methods of using the same for cancer therapy
A compound and unsubstituted technology, applied in bicyclic pyridine composition and its use in the field of cancer treatment, can solve problems such as poor pharmacokinetics
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Embodiment 1
[0160] Example 1. Thienopyridine derivatives inhibit CDK8 / 19 activity in a cell-based assay.
[0161] NFκB activity analysis. We used cell-based assays to measure inhibition of CDK8 / 19 activity by thienopyridine derivatives. This analysis is based on the role of CDK8 / 19 in NFκB-driven transcription (Li et al., Characterizing CDK8 / 19 Inhibitors through a NFκB-Dependent Cell-Based Assay, Cells 2019, 8(10), 1208), measuring CDK8 / 19 pairs from 293 Effects of the NFκB-dependent promoter on the expression of the firefly luciferase reporter gene in cells. The lentiviral vector pHAGE-NFKB-TA-LUC-UBC-dTomato-W (Addgene #49335) was introduced into 293 cells to establish a clonal cell line showing the strongest induction of luciferase expression upon TNFα treatment and used as a reporter gene cell line. As a control for the CDK8 / 19 dependence of NFKB inhibition, we also introduced the same reporter construct into 293 cells with CRISPR / CAS9 knockout of both CDK8 and CDK19.
[0162] NF...
Embodiment 2
[0166] Example 2. Kinome profiling of thienopyridine derivatives.
[0167] Table 2 shows through KINOMEscan TM Kinome profiles of 15u_D6 and 15u measured at 2000 nM concentration by site-directed competition binding assay. Compounds that bind to the active site of the kinase and directly (sterically) or indirectly (allosterically) prevent binding of the kinase to the immobilized ligand will reduce the amount of kinase trapped on the solid support. In contrast, test molecules that did not bind the kinase had no effect on the amount of kinase captured by the solid support. Screening "hits" are determined by measuring the amount of kinase captured in test and control samples using a quantitative, precise and ultrasensitive qPCR method that detects the relevant DNA marker. In a similar manner, dissociation constants (Kd) for test compound-kinase interactions were calculated by measuring the amount of kinase trapped on the solid support as a function of test compound concentratio...
Embodiment 3
[0186] Example 3. Pharmacokinetics of Thienopyridine Derivatives
[0187] Pharmacokinetic (PK) analysis. To measure pharmacokinetics (PK) in mice, thienopyridine derivatives were dissolved in 5% glucose and administered to female FVB mice under different dosing conditions; blood samples were collected at different time points and analyzed by LC / MS / MS measures compound concentrations in serum.
[0188] PK results. Figures 2A-2D and Table 4 shows the PK profiles and calculated parameters for 15k, 15v and 15u, which were mixed and administered intravenously (i.v.) to mice at 0.5 mg / kg of each compound. In this analysis, such as area under the curve (AUC) and elimination half-life (t 1 / 2 ), 15u shows the highest i.v. utilization and 15k shows the lowest i.v. utilization.
[0189] Table 4: Comparison of Pharmacokinetics of 15k, 15v and 15u administered intravenously
[0190] 15k 15v 15u C 0 (ng / mL)
168.0 233.9 328.3 V d (L / kg)
2.98 2.14 1...
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