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

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(3H)-one has been identified as an excellent hinge binding moiety for multi-target inhibitors of angiogenic VEGFR-2, Tie-2, and EphB4.

First‐in‐human, phase I study of PF‐06647263, an anti‐EFNA4 calicheamicin antibody–drug conjugate, in patients with advanced solid tumors

“…30 In a recent study, the multitarget receptor tyrosine kinase inhibitor of VEGFR-2, TIE-2, and EphB4 QDAU5 was shown to mediate antiangiogenesis and anticancer activity in vitro and an in vivo MCF-7 breast cancer xenograft model. 31 In conclusion, the anti-EFNA4 ADC PF-06647263 evaluated in this study has shown manageable safety and a favorable PK profile at the RP2D administered once weekly. Although preliminary evidence of antitumor activity was observed in patients with heavily pretreated TNBC and ovarian cancer, study enrollment was terminated due to the limited response to adequate exposure of PF-06647263 in patients with TNBC.…”

“…Initial phase I findings with JI‐101 combined with everolimus in patients with advanced ovarian cancer showed that combination treatment was well tolerated, but associated with limited antitumor activity in this patient population . In a recent study, the multitarget receptor tyrosine kinase inhibitor of VEGFR‐2, TIE‐2, and EphB4 QDAU5 was shown to mediate antiangiogenesis and anticancer activity in vitro and an in vivo MCF‐7 breast cancer xenograft model …”

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

“…Type I 1/2 inhibitors interact with the same site as type I and extend to target the back pocket. VEGFR‐2, Tie‐2, and EphB4 share a basic architecture for construction, namely the hinge region, gatekeeper region, conserved Glu‐ and DFG‐motifs, and selective site . We have developed a novel multiple RTKI (BPS‐7) matching to the active site of these RTKs …”

“…VEGFR-2, Tie-2, and EphB4 share a basic architecture for construction, namely the hinge region, gatekeeper region, conserved Glu-and DFG-motifs, and selective site. 192 We have developed a novel multiple RTKI (BPS-7) matching to the active site of these RTKs. 193 Type I inhibitors bind to RTKs through one to three hydrogen bonds with the hinge region and hydrophobic interactions in the adenine ring domain.…”

5‐(4‐Methoxybenzylidene)thiazolidine‐2,4‐dione‐derived VEGFR‐2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluations

“…[ 28 ] Furthermore, the analysis of the X‐ray structure of various inhibitors bound to VEGFR‐2 confirmed the sufficient space available for various substituents around the terminal heteroaromatic ring. [ 29–31 ]…”