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  • br Results and discussion br Conclusions As

    2022-01-03


    Results and discussion
    Conclusions As described above, the SAR study based on compound 1 led to the identification of compound 4 as an ideal inhibitor. An enzyme level investigation showed that 4 is a more potent and selective FGFRs tyrosine kinase inhibitor than is Ponatinib. In addition, the use of 4 as a drug could be associated with a lower level of adverse side effects caused by VEGFR and EGFR inhibition. Finally, the results of further studies show that 4 has favorable pharmacokinetic properties in mice and better antitumor activity than does Ponatinib in a FGFR2-driven SNU-16 xenograft model. The combined observations indicate that 4 is an excellent starting point for optimization studies targeted at the development of clinical candidates for treatment of patients with FGFRs driven cancer.
    Experimental section
    Statistical analysis Data of in vitro and in vivo efficacy are presented as the mean ± SD, and significance was determined by Student's t-test. Differences were considered statistically significant at ***P < 0.001, **P < 0.01.
    Acknowledgments We are grateful for financial support from the National Natural Science Foundation of China (Grant No. 81225022, 81473243, 81321092); The National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” of China (Grant No. 2012ZX09301001-007). SA-SIBS Scholarship Program is also gratefully acknowledged.
    Introduction Bone marrow contains many cell types including mesenchymal stromal somatostatin agonist (MSCs). The MSCs are a rare population, counting only 0,001% of bone marrow nucleated cells (Chamberlain et al., 2007). These cells can be isolated and enriched by plastic adherence in culture and identified on the basis of surface marker expression. MSCs are CD73 and CD105 positive and lack the expression of hematopoietic markers such as CD14, CD34 and CD45 (Dominici et al., 2006, Peister et al., 2004). They can also be defined by their multilineage differentiation capacity. somatostatin agonist In living organism, and also in vitro, MSCs can differentiate into many cell types including osteoblasts and adipocytes (Chamberlain et al., 2007, Miraoui et al., 2009). The cells retain their capacity of proliferating and differentiating to a certain extent and therefore they can be used in culture for several passages. However, primary cells display a high variation between species and individuals (Chamberlain et al., 2007, Dominici et al., 2006, Peister et al., 2004) and the reproducibility of the results has often been poor. Therefore, there is a need for MSC cell line models capable of unlimited proliferation and multi lineage differentiation. The fibroblast growth factor (FGF) family consists of 23 members which can be divided into 6 subfamilies. They bind to FGF-receptors (FGFRs) 1–4 (Beenken and Mohammadi, 2009, Ornitz and Itoh, 2015) with different binding affinities but only FGF1 and FGF2 are able to bind and activate all the receptors (Beenken and Mohammadi, 2009, Ornitz and Itoh, 2015). Activation of FGFRs leads to phosphorylation and action of several molecules on the downstream signaling pathways including ERK/MAPK, PI3K/AKT and PLCy. The FGFs and FGFRs are known to be important for many developmental processes (Beenken and Mohammadi, 2009, Ornitz and Itoh, 2015) and they also have a role in MSC differentiation (Du et al., 2012). Mutations in the FGFR genes can lead to skeletal defects such as craniosynostosis and chondrodysplasias (Miraoui et al., 2009, Du et al., 2012, Trueb, 2011). Particularly FGFR2 has been found to be an important driver of osteoblast differentiation (Miraoui et al., 2009, Du et al., 2012). FGFs and FGFRs are also expressed in human white and brown adipose tissue (Hutley et al., 2011, Widberg et al., 2009). Silencing FGFR1 expression as well as the use of dominant-negative form of FGFR1 resulted in the inhibition of adipocyte differentiation in vitro, suggesting the importance of FGFR1 in the process (Patel et al., 2005).