4-Aminopyrazolopyrimidine scaffold and its deformation in the design of tyrosine and serine/threonine kinase inhibitors in medicinal chemistry.

The 4-Aminopyrazolopyrimidine scaffold has been an interesting pharmacophore since the disclosure of the intimate connection between small-molecule inhibitors and the treatment of diseases. Modification of the 4-aminopyrazolopyrimidine scaffold according to different targets, especially tyrosine kinase and serine/threonine kinase, has resulted in a variety of small-molecule inhibitors. Kinase inhibitors with 4-aminopyrazolopyrimidine derivatives as scaffolds have been widely applied in the treatment of diseases. In this article, we summarized the reports on 4-aminopyrazolopyrimidine as well as its deformation and the application of its derivatives in designing small-molecule inhibitors and the treatment of diseases.

LncRNA PVT1 Regulates TRPS1 Expression in Breast Cancer by Sponging miR-543.

BACKGROUND: Breast cancer is the most common female malignancy with high invasion and metastasis abilities. Studies have shown that long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 gene (PVT1) is an oncogene and is positively correlated with progression and metastasis of breast tumors. However, the detailed mechanism of PVT1 in breast cancer tumorigenesis is not fully understood. METHODS: Real-time polymerase quantitative chain reaction (RT-qPCR) was performed to identify the expression levels of PVT1, miR-543 and trichorhinophalangeal syndrome-1 gene (TRPS1) in breast cancer tissues and cells. Cell proliferation was measured by plate clone formation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazol-3-ium bromide (MTT) assay. Apoptosis and motility of MCF-7 and MDA-MB-436 cells were assessed with flow cytometry assay and transwell migration and invasion analyses, respectively. In addition, a model was established to probe the function of PVT1 silencing in vivo. The target relationship among PVT1, miR-543 or TRPS1 was confirmed by dual-luciferase reporter analysis, RNA immunoprecipitation (RIP) and RNA pull down assays. The protein expression level of TRPS1 was evaluated with Western blot assay. RESULTS: PVT1 expression was upregulated in breast cancer tissues and cell lines. In addition, PVT1 silencing inhibited breast cancer cell growth and motility, while increased apoptosis. Meanwhile, the effects of PVT1 or miR-543 could be reversed by introducing overexpressed plasmid of miR-543 or TRPS1 in breast cancer cell lines, respectively. CONCLUSION: Knockdown of PVT1 repressed breast cancer cell growth and motility, and induced apoptosis in vitro and reduced tumor volume and weight in vivo. Mechanically, the overexpression of PVT1 enhanced TRPS1 level by negatively targeted miR-543 in breast cancer.

Annexin A7 is correlated with better clinical outcomes of patients with breast cancer.

The clinical prognosis of breast cancer (BC) patients remains poor. Studies on BC microarrays GSE37751, GSE7390, and GSE21653 were reanalyzed to characterize the expressions of annexin A7 (ANXA7) in BC patients and the corresponding normal breast tissues and the correlation between ANXA7 expression and clinical characteristics and survivals of BC patients. Gene set enrichment analysis (GSEA) was applied to investigate the exact mechanisms as for the expression of ANXA7 and the proliferation of BC cells. The level of ANXA7 expression was significantly decreased in BC patients than that in normal controls (P < .0001). BC patients in the ANXA7 high-expression group were associated with better clinical features such as tumor size; histopathological grading; estrogen receptors; and clinical risk groups according to St Gallen criteria, Nottingham prognostic index criteria, and Veridex signature compared with those in the ANXA7 low-expression group. Higher expression of ANXA7 predicted better prognosis of BC patients. The result of GSEA indicated that ANXA7 might inhibit the proliferation of BC cells through biological processes involved in androgen response, heme metabolism, and oxidative phosphorylation. The messenger RNA and protein levels of ANXA7 were decreased in BC tissues compared with those in normal breast tissues. Our results proved that ANXA7 was downregulated in BC cells and that a higher expression of ANXA7 was associated with better prognosis of BC patients.

Expression of Fibroblast Growth Factor 5 (FGF5) and Its Influence on Survival of Breast Cancer Patients.

BACKGROUND The clinical outcome of patients with breast cancer (BC) remains poor. MATERIAL AND METHODS We analyzed BC microarray studies GSE37751, GSE7390, and GSE21653 to investigate the expression of FGF5 gene between BC patients and their normal counterparts and the relationship between FGF5 expression and age, tumor size, histopathological grading, estrogen receptors, clinical risk group according to St Gallen criteria, clinical risk group according to NPI criteria, clinical risk group according to Veridex signature, distant metastasis-free survival (DMFS), time to distant metastasis (TDM), disease-free survival (DFS), and overall survival (OS) of BC patients. Gene set enrichment analysis (GSEA) was used to investigate the exact mechanisms. RESULTS FGF5 expression was significantly upregulated in BC patients relative to that in normal controls (P<0.0001). BC patients in the FGF5 low-expression group were correlated with better clinical characteristics, including tumor size, histopathological grading, estrogen receptors, clinical risk group according to St Gallen criteria, NPI criteria and Veridex signature, DMFS, TDM, and DFS compared with those in the FGF5 high-expression cohort. The result of GSEA indicated that FGF5 inhibits the proliferation of BC cells via ultraviolet response and TGF-b signaling. Quantitative PCR verified that FGF5 was overexpressed in patients with BC. CONCLUSIONS Our results suggest that FGF5 is an independent protective factor for BC patients.