Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure-activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFR simultaneously . Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.

In-line monitoring of blending process of Zhongsheng pill powder using miniature near-infrared analyzer / 中国中药杂志

<p><b>OBJECTIVE</b>To establish a simple and rapid method based on diffuse reflectance NIR spectra to in-line monitor the blending process of Zhongsheng pill powder.</p><p><b>METHOD</b>Zhongsheng pill powder consisted of Zhongsheng spray powder, artificial cowbezoar powder and bile arisaema powder. By means of a revolutionary miniature near-infrared analyzer mounted onto the blender, the powder homogeneity was determined in real time with noninterference. The moving block standard deviation (MBSD) method was used to identify the end point of blending process, providing real-time data and instant feedback about the blending course. Evaluation of blend uniformity was carried out by stratified in-process sampling, and the content of baicalin in samples was determined by high performance liquid chromatography (HPLC).</p><p><b>RESULT</b>The results calculated through MBSD method were generally coincided with HPLC analysis. Blend homogeneity was assumed to be reached when the standard deviations between spectra approached 0.002, and RSD values of baicalin content in samples from six positions were lower than 5%. Moreover, stratified in-process sampling has significant influence on blending process when the powder loading volume was small.</p><p><b>CONCLUSION</b>Based on this study, NIR spectroscopy can be possibly extended to be applied in blending process of Zhongsheng pill powder, ensuring a remarkable saving of time and manpower employed and creating a reliable and efficient process measurement technology.</p>