Aurora kinase inhibitors: a patent review (2014-2020).

Introduction: Aurora kinases are a family of serine/threonine kinases, and promote mitotic spindle assembly by regulating centrosome duplication and separation. Aurora kinases are overexpressed in a variety of tumor cell lines, thus, the use of Aurora kinase small-molecule inhibitors has become a potential treatment option for cancer.Areas covered: As a continuing review of Aurora kinase inhibitors and their patents published in 2009, 2011 and 2014. Herein, we updated the information for Aurora kinase inhibitors in clinical trials and the patents filed from 2014 to 2020. PubMed, Scopus, SciFinder, and www.clinicaltrials.gov databases were used for searching the clinical information and patents of Aurora kinase inhibitors.Expert opinion: Even though Aurora A or B selective as well as pan inhibitors show preclinical and clinical efficacy, so far, no Aurora kinase inhibitor has been approved for clinical use. Preliminary evidence suggested that highly selective Aurora kinase or multi-target inhibitors as a single agent as well as in combination therapy are still the current main development trend of Aurora kinase inhibitors.

Design, synthesis and biological evaluation of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol-1-yl)acetamide derivatives as potent VEGFR-2 inhibitors.

Vascular endothelial growth factor-2 (VEGFR-2) plays a pivotal role in tumor angiogenesis. Herein, a library of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol -1-yl)acetamide derivatives were designed and synthesized as VEGFR-2 inhibitors based on scaffold hopping strategy. These compounds exhibited the excellent inhibitory in both VEGFR-2 and tumor cells proliferation. Especially, compound W13 possessed potent VEGFR-2 inhibition with IC50 = 1.6 nM and anti-proliferation against HGC-27 tumor cells with IC50 = 0.36 ± 0.11 µM, as well as less toxicity against normal GES-1 cells with IC50 = 187.46 ± 10.13 µM. Moreover, W13 obviously inhibited colony formation, migration and invasion of HGC-27 cells by adjusting the expression of MMP-9 and E-cadherin, and induced HGC-27 cells apoptosis by increasing ROS production and regulating the expression of apoptotic proteins. Furthermore, W13 blocked the PI3K-Akt-mTOR signaling pathway in HGC-27 cells. In addition, anti-angiogenesis of W13 was proved by inhibiting tube formation and the expression of p-VEGFR-2 in HUVEC cells. All the results demonstrated that W13 could be developing as a promising anticancer agent for gastric cancer therapy.