Discovery of SPH5030, a Selective, Potent, and Irreversible Tyrosine Kinase Inhibitor for HER2-Amplified and HER2-Mutant Cancer Treatment.

Small-molecule irreversible tyrosine kinase inhibitors as high potent agents have led to improvements in disease-free and overall survival in patients with HER2-amplified cancer. The approved irreversible HER2 inhibitors, neratinib and pyrotinib, both lack HER2 selectivity, leading to off-target adverse events in patients. The development of HER2 mutation during treatment also hampers the progress of the treatment. We used a molecular hybridization strategy for structural optimizations, in conjunction with in vitro and in vivo drug-like property screening, to obtain a clinical candidate SPH5030. Overall, SPH5030 showed excellent activities against four frequent kinds of HER2 mutants and high relative HER2 selectivity compared with neratinib and pyrotinib, good pharmacokinetic characteristics with desirable bioavailabilities, and significant in vivo antitumor efficacy in xenograft mouse models, especially in a HER2 mutation A775_G776insYVMA xenograft mouse model with its potency much higher than those of neratinib and pyrotinib.

Simultaneous enantioseparation of antiparkinsonian medication Rotigotine and related chiral impurities by capillary zone electrophoresis using dual cyclodextrin system.

A dual cyclodextrin (CD) system consisting of sulfated beta-CD (S-beta-CD) and methyl-beta-CD (M-beta-CD) modified capillary zone electrophoresis (CZE) method was proposed to separate the antiparkinsonian drug Rotigotine ((-)-(S)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin) and related chiral impurities (2-(N-propylamino)-5-hydroxytetralin, 2-(N-propylamino)-5-methoxytetralin). The method was optimized by varying the CD type, the buffer pH, individual CD concentration of the dual system and the ionic strength of background electrolyte. Under the optimum conditions, i.e. 2% (w/v) S-beta-CD and 2% (w/v) M-beta-CD in 100mM sodium phosphate (pH 2.5) as the running buffer, separation voltage -20 kV, detected at 200 nm and temperature controlled at 20 degrees C, a satisfactory separation of the six analytes was accomplished. The optimized method was validated for specificity, precision, linearity, accuracy and stability using sodium benzenesulfonate as the internal standard. The relative standard deviation for migration time was less than 0.58%, and 3.78% for peak area ratio. The linearity ranged from 0.005 to 0.25 mM. The recovery ranged from 95.9% to 108.3%. The limits of detection and limits of quantification for each enantiomer were 0.003 and 0.01 mM, respectively. This method was utilized for evaluating the chiral purity of five batches of Rotigotine.