Discovery of novel anti-angiogenesis agents. Part 9: Multiplex inhibitors suppressing compensatory activations of RTKs

Aberrant angiogenesis is a hallmark of various diseases including cancers. VEGFR-2 inhibitors have been utilized as anti-angiogenic agents for several years. However, compensatory activation of various receptor tyrosine kinases (RTK) could induce the occurrence of resistance. We previously reported a series of multi-target inhibitors of VEGFR-2, Tie-2, and EphB4 as anti-angiogenic agents. These inhibitors might be a promising strategy to overcome the resistance induced by compensatory activation. In order to expand the structural diversity of these multiple RTK inhibitors, we described herein the design, synthesis, and evaluation of a novel class of triplet VEGFR-2/TIE-2/EphB4 inhibitors. The biological evaluation indicated that five compounds (6b, 6d, 6e, 7e, and 7g) exhibited simultaneous VEGFR-2/Tie-2/EphB4 inhibitory activities with IC50 values less than 50 nM. [Display omitted] As a continuation to our previous research, a series of novel anti-angiogenic agents with simultaneous RTK inhibition profile were developed. •Multi-target inhibitors based on the compensatory of angiogenic RTKs.•Several compounds exhibited simultaneously inhibitory potency.•1,2,3-Triazole is a novel scaffold of triple RTK inhibitors.