VEGFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012-2016)

ABSTRACT

Introduction: Angiogenesis is an important component of certain normal physiological processes, but aberrant angiogenesis contributes to some pathological disorders and in particular to tumor growth. Activation of vascular endothelial growth factor receptor-2 (VEGFR-2) by vascular endothelial growth factor (VEGF) is a critical step in the signal transduction pathway that initiates tumor angiogenesis. Inhibition of angiogenesis via blocking VEGF/VEGFR-2 signaling pathway has emerged as a potential approach to anticancer therapy. Indeed, this approach has recently been clinically validated with the approvals of VEGFR-2 inhibitors.

Areas covered: This review accounts for small-molecule inhibitors and antibodies of VEGFR-2 reported in the patent literature covering between January 2012 and June 2016, and their potential use as therapeutics for cancers, angiogenesis-related disorders and inflammatory diseases.

Expert opinion: Despite the attractiveness of anti-angiogenic therapy by VEGF inhibition alone, several issues may limit this approach. VEGF expression levels can be elevated by numerous diverse stimuli such as the activation of other RTK signaling transduction pathway. Therefore, the development of multi-targeted tyrosine kinase inhibitors and the strategy of using these agents in conjunction with other anti-cancer agents are recent interesting therapeutic approaches that could give promising results.

KEYWORDS:

• Angiogenesis
• VEGFR-2
• inhibitors
• patent

Article highlights

• Vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors are an efficient class of tumor therapy currently under clinical investigation.

• The patents’ production in the field of VEGFR-2 inhibitors from 2012 to 2016 was examined.

• A large number of patents described small molecules bearing different structural scaffolds including urea, quinolone, indolin-one, pyridine and pyrimidine and biological macromolecules.

• Some of these compounds were able to inhibit VEGFR-2 selectively while some of them were capable of inhibiting varieties of protein kinases. They showed potent anti-angiogenesis or anti-inflammatory or anti-cancer activity both in vitro and in vivo.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Additional information

Funding

This work was supported by National Natural Science Foundation of China (Grant No. 21102182), Natural Science Foundation of Jiangsu Province (Grant No. BK2012760) and Excellent Science and Technology Innovation Team of Jiangsu Province Universities in 2015, China.