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1.
Expert Opin Ther Pat ; 27(9): 987-1004, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28621580

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.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Neovascularization, Pathologic/drug therapy , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Drug Design , Humans , Neoplasms/blood supply , Neoplasms/drug therapy , Neovascularization, Pathologic/pathology , Patents as Topic , Protein Kinase Inhibitors/pharmacology , Signal Transduction/drug effects
2.
Eur J Med Chem ; 109: 1-12, 2016 Feb 15.
Article in English | MEDLINE | ID: mdl-26741358

ABSTRACT

A single agent that simultaneously inhibits multiple targets may offer greater therapeutic benefits in cancer than single-acting agents through interference with multiple pathways and potential synergistic action. In this work, a series of hybrids bearing N-phenylquinazolin-4-amine and hydroxamic acid moieties were designed and identified as dual VEGFR-2/HDAC inhibitors. Compound 6fd exhibited the most potent inhibitory activity against HDAC with IC50 of 2.2 nM and strong inhibitory effect against VEGFR-2 with IC50 of 74 nM. It also showed the most potent inhibitory activity against a human breast cancer cell line MCF-7 with IC50 of 0.85 µM. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the active binding sites of VEGFR-2 and HDLP ((Histone Deacetylase-Like Protein), which demonstrates that compound 6fd is a potential agent for cancer therapy deserving further researching.


Subject(s)
Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Amination , Cell Proliferation/drug effects , Drug Design , Female , Histone Deacetylases/metabolism , Humans , MCF-7 Cells , Molecular Docking Simulation , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/metabolism
3.
Bioorg Med Chem Lett ; 25(22): 5137-41, 2015 Nov 15.
Article in English | MEDLINE | ID: mdl-26475519

ABSTRACT

A series of hybrids derived from 4-anilinoquinazoline and hydroxamic acid were designed, synthesized, and evaluated as dual inhibitors of vascular endothelia growth factor receptor-2 (VEGFR-2) tyrosine kinase and histone deacetylase (HDAC). Most of these compounds exhibited potent HDAC inhibition and moderate VEGFR-2 inhibition. Among them, compound 6l exhibited the most potent inhibitory activities against VEGFR-2 (IC50=84 nM) and HDAC (IC50=2.8 nM). It also showed the most potent antiproliferative ability against MCF-7, a human breast cancer line, with IC50 of 1.2 µM. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction of compound 6l at the active binding sites of VEGFR-2 and HDAC.


Subject(s)
Antineoplastic Agents/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Catalytic Domain , Cell Line, Tumor , Drug Screening Assays, Antitumor , Histone Deacetylase Inhibitors/chemical synthesis , Humans , Molecular Docking Simulation , Protein Kinase Inhibitors/chemical synthesis , Quinazolines/chemical synthesis , Structure-Activity Relationship
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