Design, synthesis, anticancer evaluation and molecular docking of new V600EBRAF inhibitors derived from pyridopyrazinone

Design and synthesis of some new pyridopyrazinone derivatives as anti-proliferative agents is described. The cytotoxic activities of the synthesized compounds against melanoma cell line (LOXIMVI), ovarian cell line (OVCAR3), thyroid cell lines (CAL62, FTC133, BCPAP and ML1) and colon cell lines (HT29 and HCT116) were investigated. Results revealed that most compounds were active and compound 3d was the most active one. It exhibited promising activity against all tested cell lines. In addition, in vitro kinase assay against both WTBRAF and V600EBRAF was performed for all synthesized compounds. Furthermore, molecular docking of tested compounds was established with active site of V600EBRAF kinase domain. Results of kinase inhibition assay and molecular docking revealed that, compounds 1, 3d, e, h, i, 5d, e and 6b were potent inhibitors for V600EBRAF kinase enzyme involved in number of cancer types as melanoma, ovarian and thyroid cancer. The newly synthesized pyridopyrazinones substituted with different substituents at C-3 or fused with triazine heterocycle at C-3 and C-4 afforded potent V600EBRAF inhibitors and exhibited promising cytotoxic activities against different cancer types such as melanoma, ovarian, thyroid and colon cancer

Characterization of 107 Genomic DNA Reference Materials for CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1: A GeT-RM and Association for Molecular Pathology Collaborative Project

Pharmacogenetic testing is becoming more common; however, very few quality control and other reference materials that cover alleles commonly included in such assays are currently available. To address these needs, the Centers for Disease Control and Prevention's Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetic testing community and the Coriell Cell Repositories, have characterized a panel of 107 genomic DNA reference materials for five loci (CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1) that are commonly included in pharmacogenetic testing panels and proficiency testing surveys. Genomic DNA from publicly available cell lines was sent to volunteer laboratories for genotyping. Each sample was tested in three to six laboratories using a variety of commercially available or laboratory-developed platforms. The results were consistent among laboratories, with differences in allele assignments largely related to the manufacturer's assay design and variable nomenclature, especially for CYP2D6. The alleles included in the assay platforms varied, but most were identified in the set of 107 DNA samples. Nine additional pharmacogenetic loci (CYP4F2, EPHX1, ABCB1, HLAB, KIF6, CYP3A4, CYP3A5, TPMT, and DPD) were also tested. These samples are publicly available from Coriell and will be useful for quality assurance, proficiency testing, test development, and research