Background: Mutant-selective IDH1 inhibitors are potential cancer therapeutics, but the mechanistic basis for their selectivity is not yet well understood. Results: Inhibitor binding modes and kinetic mechanisms were characterized. Conclusion:The inhibitors selectively inhibit mutant IDH1 by interacting with a magnesium-binding residue. Significance: Targeting metal-binding residues with drug-like small molecules is a feasible strategy for IDH1 inhibition.

Structure–activity relationship studies of the natural product cystobactamid at four different positions led to novel imaging probes and analogs with superior antibacterial activities and in vivo efficacy.

No abstract

Three standardised, capillary zone electrophoresis-electrospray ionisation mass spectrometry (CZE-ESI-MS) methods were developed for the analysis of six drug candidates and their respective process-related impurities comprising a total of 22 analytes with a range of functional groups and lipophilicities. The selected background electrolyte conditions were found to be: 60/40 v/v 10 mM ammonium formate pH 3.5/organic, 60/40 v/v 10 mM ammonium acetate pH 7.0/organic and 10 mM piperidine, pH 10.5, where the organic solvent is 50/50 v/v methanol/acetonitrile. The coaxial sheath flow consisted of either 0.1% v/v formic acid in 50/50 v/v methanol/water, or 10 mM ammonium acetate in 50/50 v/v methanol/water, depending on the mixture being analysed. Factor analysis and informational theory were used to quantify the orthogonality of the methods and predict their complementarities. The three selected CZE-ESI-MS methods allowed the identification of 21 out of 22 of all the drug candidates and their process-related impurities and provided orthogonality with four established high-performance liquid chromatography-mass spectrometry (HPLC-MS) methods. These methodologies therefore form the basis of a generic approach to impurity profiling of pharmaceutical drug candidates and can be applied with little or no analytical method development, thereby offering significant resource and time savings.

Open-tubular CEC and non-aqueous CE (NACE) methods were developed for the analysis of six pharmaceutical compounds and their respective process-related impurities, comprising 22 analytes in total with a range of functional groups and lipophilicities. These methods were assessed for orthogonality of analyte separation with respect to existing CZE-ESI-MS and HPLC-ESI-MS methods, in order to complement a generic analytical strategy for impurity profiling of pharmaceutical compounds. Open-tubular CEC, using etched and chemically modified capillaries, induced weak reversed-phase-type interactions between some of the analytes and the bonded phases (0.811