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Pemigatinib (PMB) is a small molecule inhibitor of fibroblast growth factor receptor 1 (FGFR1), FGFR2 and FGFR3. On April 17, 2020, the US Food and Drug Administration granted accelerated approval for PMB for the treatment of adults with previously treated, unresectable metastatic or locally advanced cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement. PMB is considered the first targeted treatment for cholangiocarcinoma approved in the US. In this study, in silico prediction of PMB metabolic stability was done using the WhichP450 module of the StarDrop software package. Further, an LC-MS/MS analytical method was developed for PMB quantification in human liver microsomes (HLM) to experimentally assess metabolic stability. PMB and flavopiridol (FVL), used as an internal standard IS, were resolved using an isocratic mobile phase and a C18 stationary phase. The LC-MS/MS method showed linearity in the range of 5 to 500 ng mL -1 in an HLM matrix ( R 2 = 0.9995). The lower limit of quantification (LLOQ) was 5 ng mL -1 , indicating sensitivity. The inter- and intra-day accuracy and precision were within a variability of 10, confirming the reproducibility of the method. The measured in vitro half-life and intrinsic clearance of PMB were 27.29 min and 25.40 μL min -1 mg -1 , respectively. PMB showed a moderate extraction ratio suggesting good bioavailability. The developed analytical method is the first LC-MS/MS method specific for PMB quantification with application to metabolic stability assessment., Competing Interests: The authors report no conflicts of interest for this work., (This journal is © The Royal Society of Chemistry.)

A new series of 3-methylquinoxaline-based derivatives having the same essential pharmacophoric features as VEGFR-2 inhibitors have been synthesized and evaluated for their antiproliferative activities against two human cancer cell lines, MCF-7 and HepG-2. Compounds 15b and 17b demonstrated a significant antiproliferative effect with IC 50 ranging from 2.3 to 5.8 μM. An enzymatic assay was carried out for all the tested candidates against VEGFR-2. Compound 17b was the most potent VEGFR-2 inhibitor (IC 50 = 2.7 nM). Mechanistic investigation including cell cycle arrest and apoptosis was performed for compound 17b against HepG-2 cells, and the results revealed that 17b induced cell apoptosis and arrested cell cycle in the G2/M phase. Moreover, apoptosis analyses were conducted for compound 17b to evaluate its apoptotic potential. The results showed upregulation in caspase-3 and caspase-9 levels, and improving the Bax/Bcl-2 ratio by more than 10-fold. Docking studies were performed to determine the possible interaction with the VEGFR-2 active site. Further docking studies were carried out for compound 17b against cytochrome P450 to present such compounds as non-inhibitors. In silico ADMET, toxicity, and physico-chemical properties revealed that most of the synthesized members have acceptable values of drug-likeness. Finally, DFT studies were carried out to calculate the thermodynamic, molecular orbital and electrostatic potential properties., Competing Interests: There is no conflict of interest. Many thanks for Dr Mohamed R. Elnagar, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt for his valuable technical assistance., (This journal is © The Royal Society of Chemistry.)

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in a contagious respiratory tract infection that has become a global burden since the end of 2019. Notably, fewer patients infected with SARS-CoV-2 progress from acute disease onset to death compared with the progression rate associated with two other coronaviruses, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Several research organizations and pharmaceutical industries have attempted to develop successful vaccine candidates for the prevention of COVID-19. However, increasing evidence indicates that the SARS-CoV-2 genome undergoes frequent mutation; thus, an adequate analysis of the viral strain remains necessary to construct effective vaccines. The current study attempted to design a multi-epitope vaccine by utilizing an approach based on the SARS-CoV-2 structural proteins. We predicted the antigenic T- and B-lymphocyte responses to four structural proteins after screening all structural proteins according to specific characteristics. The predicted epitopes were combined using suitable adjuvants and linkers, and a secondary structure profile indicated that the vaccine shared similar properties with the native protein. Importantly, the molecular docking analysis and molecular dynamics simulations revealed that the constructed vaccine possessed a high affinity for toll-like receptor 4 (TLR4). In addition, multiple descriptors were obtained from the simulation trajectories, including the root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), and radius of gyration ( R g ), demonstrating the rigid nature and inflexibility of the vaccine and receptor molecules. In addition, codon optimization, based on Escherichia coli K12, was used to determine the GC content and the codon adaptation index (CAI) value, which further followed for the incorporation into the cloning vector pET28+(a). Collectively, these findings suggested that the constructed vaccine could be used to modulate the immune reaction against SARS-CoV-2., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)