Recent progress on vascular endothelial growth factor receptor inhibitors with dual targeting capabilities for tumor therapy

Abstract

Vascular endothelial growth factor receptors (VEGFRs) are a family of receptor protein tyrosine kinases that play an important role in the regulation of tumor-induced angiogenesis. Currently, VEGFR inhibitors have been widely used in the treatment of various tumors. However, current VEGFR inhibitors are limited to a certain extent due to limited clinical efficacy and potential toxicity, which hinder their clinical application. Thus, the development of new strategies to improve the clinical outcomes and minimize the toxic effects of VEGFR inhibitors is required. Given the synergistic effect of VEGFR and other therapies in tumor development and progression, VEGFR dual-target inhibitors are becoming an attractive approach due to their favorable pharmacodynamics, low toxicity, and anti-resistant effects. This perspective provides an overview of the development of VEGFR dual-target inhibitors from multiple aspects, including rational target combinations, drug discovery strategies, structure-activity relationships and future directions.

Keywords: Antiangiogenesis treatment; Antitumor drugs; Dual inhibitor; VEGFR kinase.

Fig. 1

A Schematic representation of the VEGFR protein domain structure; B the overlap of crystal structures of VEGFR3 (pink), VEGFR2 (PDB ID: 3WZE, brown) and VEGFR1 (PDB ID: 3HNG, blue). The structure of VEGFR1 and VEGFR2 was utilized to construct the homology model of human VEGFR3; C mechanisms of tumor angiogenesis regulated by VEGFR signaling

Fig. 2

Crystal structure of the FDA-approved VEGFR inhibitors—VEGFR2 complex. The corresponding PDB codes are 3WZE (sorafenib), 3WZD (lenvatinib), 4AGC (axitinib) and 3EFL (motesanib). Hydrogen binding (black) interactions are shown as dashed lines. A The overlap of co-crystal structures of VEGFR2 with sorafenib (green), lenvatinib (orange), axitinib (gray) and motesanib (blue); B–E Binding modes of VEGFR2 with sorafenib, lenvatinib, axitinib and motesanib

Fig. 3

Chemical structures of dual VEGFR2–EGFR inhibitors 14, 16, 17 and 19–25 and their inhibitory activities against VEGFR2 and EGFR

Fig. 4

Chemical structures of dual VEGFR2–FGFR inhibitors 26–30 and their inhibitory activities against VEGFR2 and FGFR

Fig. 5

Structural formulae of dual VEGFR2/c-Met inhibitors

Fig. 6

Chemical structure and properties of dual VEGFR–c-Met inhibitors 41–48

Fig. 7

Chemical structures of dual VEGFR–c-Met inhibitors 49–58 and their inhibitory activities against VEGFR2 and c-Met

Fig. 8

Chemical structures of dual VEGFR–BRAF inhibitors 59, 60 and 62 and their inhibitory activities against VEGFR2 and BRAF

Fig. 9

Chemical structures of dual VEGFR–HDAC inhibitors 64 and 65 and their inhibitory activities against VEGFR2 and HDAC

Fig. 10

Chemical structures of dual VEGFR–HDAC inhibitors 67–70 and their inhibitory activities against VEGFR2 and HDAC

Fig. 11

Chemical structures of dual VEGFR–tubulin inhibitors 73, 74, 77, 78, 79 and 80 and their inhibitory activities against VEGFR2 and tubulin polymerization (TPI)

Fig. 12

Chemical structures of dual VEGFR–ERα inhibitors 83–86, 88 and 89 and their inhibitory activities against VEGFR2 and ERα

Fig. 13

Chemical structure of dual VEGFR–PIM1 inhibitor 91 and its inhibitory activities against VEGFR2 and PIM1

Fig. 14

Chemical structure of dual VEGFR–RET inhibitors 92, 93, and VEGFR–AKT inhibitor 94 as well as their inhibitory activities against their target proteins