Discovery and evaluation of triple inhibitors of VEGFR-2, TIE-2 and EphB4 as anti-angiogenic and anti-cancer agents

// Lin Zhang 1,* , Yuanyuan Shan 2,* , Xingyue Ji 3 , Mengyuan Zhu 3 , Chuansheng Li 1 , Ying Sun 1 , Ru Si 1 , Xiaoyan Pan 1 , Jinfeng Wang 1 , Weina Ma 1 , Bingling Dai 1 , Binghe Wang 3 and Jie Zhang 1 1 School of Pharmacy, Health Science Center, Xi’an Jiaotong University, Xi’an, China 2 Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China 3 Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, United States * These authors contributed equally to this work and should be regarded as joint first authors Correspondence to: Jie Zhang, email: // Binghe Wang, email: // Keywords : receptor tyrosine kinase, multiple inhibitors, anti-angiogenic agents, anti-cancer agents, quinazolin-4(3H)-one Received : June 15, 2017 Accepted : July 30, 2017 Published : August 08, 2017 Abstract Receptor tyrosine kinases (RTKs), especially VEGFR-2, TIE-2, and EphB4, play a crucial role in both angiogenesis and tumorigenesis. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat such pathological traits with single-target agents. Herein, we developed two classes of multi-target RTK inhibitors (RTKIs) based on the highly conserved ATP-binding pocket of VEGFR-2/TIE-2/EphB4, using previously reported BPS-7 as a lead compound. These multi-target RTKIs exhibited considerable potential as novel anti-angiogenic and anticancer agents. Among them, QDAU5 displayed the most promising potency and selectivity. It significantly suppressed viability of EA.hy926 and proliferation of several cancer cells. Further investigations indicated that QDAU5 showed high affinity to VEGFR-2 and reduced the phosphorylation of VEGFR-2. We identified QDAU5 as a potent multiple RTKs inhibitor exhibiting prominent anti-angiogenic and anticancer potency both in vitro and in vivo . Moreover, quinazolin-4(3 H )-one has been identified as an excellent hinge binding moiety for multi-target inhibitors of angiogenic VEGFR-2, Tie-2, and EphB4.