Research Progress of Small Molecule VEGFR/c-Met Inhibitors as Anticancer Agents (2016–Present)
Abstract
:1. Introduction
2. Chemical Design Strategies of Dual-Target VEGFR/c-Met Kinase Anticancer Inhibitors
3. Dual VEGFR and c-Met Small Molecule Inhibitors
3.1. Pyridine Derivatives
3.2. Quinoline Derivatives
3.3. Pyrrolopyridine Derivatives
3.4. Benzimidazole Derivatives
3.5. Thienopyrimidine Derivatives
3.6. Pyrrolotriazine Derivatives
3.7. Quinazoline Derivatives
3.8. Diazepine Derivatives
3.9. Pyrazolopyrimidine Derivatives
3.10. Naphthyridinone Derivatives
3.11. Triazine Derivatives
4. Structure–Activity Relationship
5. Conclusion and Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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Compounds | Structural Formula | Target | Indication | Phase | Signaling Pathway | Research and Development Company |
---|---|---|---|---|---|---|
Foretinib [45] | c-Met, VEGFR-2 (KDR), Tie-2, VEGFR-3/FLT4 | Gastric cancer and head/neck cancer | II | Protein tyrosine kinase | Exelixis | |
Golvatinib [46] | c-Met, VEGFR-2 | Head and neck cancer, liver cancer | II | Angiogenesis; protein tyrosine kinase | Eisai | |
Dovitinib [47] | FLT3, c-Kit, FGFR-1/3, VEGFR1-4, EGFR, c-Met | Solid tumors | IV | Angiogenesis | Novartis | |
Tivozanib [48] | VEGFR-1, VEGFR-2, VEGFR-3, c-Met, PDGFR, c-Kit | Advanced renal cell carcinoma | III | Angiogenesis | Aevo | |
BMS-794833 [49] | c-Met, VEGFR-2, Ron, Axl, FLT3 | Gastric cancer | I | Angiogenesis; protein tyrosine kinase | Bristol Myers Squibb | |
BMS-777607 [50] | c-Met, Axl, Ron, VEGFR-2, lck | Advanced solid tumors | II | Protein tyrosine kinase | Bristol Myers Squibb | |
MGCD-265 [51] | c-Met, Ron, VEGFR-1, VEGFR-2 | Non-small cell lung cancer | II | Angiogenesis; protein tyrosine kinase | MethylGene | |
AC480 [52] | HER1, HER2, HER4, VEGFR-2, c-Kit, Lck, MET | Advanced solid tumors | I | Angiogenesis | Ambit Biosciences | |
CP-724714 [53] | HER2/ErbB2, EGFR, VEGFR-2, c-Met | Advanced solid tumors | II | Protein tyrosine kinase | Pfizer | |
AMG-458 [54] | c-Met, VEGFR-2 | Solid tumors | Non-medicinal | Protein tyrosine kinase | Amgen |
Compound | IC50 (nM) | |||||||
---|---|---|---|---|---|---|---|---|
VEGFR-2 | c-Met | VEGFR-1 | VEGFR-3 | EGFR | IGF1-R | B-Raf | c-Kit | |
7 | 2.35 | 33.12 | 25.00 | 45.00 | 8.70 | 40.00 | 32.00 | 68.90 |
Compound | IC50 (nM) | |||||||
---|---|---|---|---|---|---|---|---|
c-Met | c-Kit | FLT3 | PDGFRα | Ron | VEGFR | EGFR | ALK | |
8 | 1.57 | 3.38 | 8.19 | 95.23 | 140.47 | 480.47 | >10000 | >10000 |
9 | 0.09 | 2.45 | 268.81 | 19.13 | 82.56 | 151.52 | 980.83 | 2840.72 |
10 | 1.98 | 380 | 400 | 242 | 375 | 689 | >10000 | >10000 |
Compound | IC50 (μM) | |||
---|---|---|---|---|
A549 | HepG2 | MCF-7 | PC-3 | |
12 | 0.82 | 1.00 | 0.93 | 0.92 |
13 | 1.30 | 1.42 | 4.53 | 4.29 |
14 | 2.19 | 1.32 | 6.27 | 4.63 |
Compound | IC50 (μM) | ||||
---|---|---|---|---|---|
c-Met | VEGFR-2 | c-Kit | FLT3 | EGFR | |
12 | 0.5 | 8.9 | 2.6 | >100 | |
13 | 0.9 | 14.4 | 3.8 | 45.0 | |
14 | 0.073 | 2.4 | 2.2 | 0.77 | >10 |
Compound | % Inhibition at 10 µM | |
---|---|---|
VEGFR-2 | c-Met | |
15 | 29.22 | 71.66 |
16 | 35.88 | 82.48 |
17 | 21.07 | 76.01 |
AG-1478 | 73.73 | 33.12 |
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Zhang, Q.; Zheng, P.; Zhu, W. Research Progress of Small Molecule VEGFR/c-Met Inhibitors as Anticancer Agents (2016–Present). Molecules 2020, 25, 2666. https://doi.org/10.3390/molecules25112666
Zhang Q, Zheng P, Zhu W. Research Progress of Small Molecule VEGFR/c-Met Inhibitors as Anticancer Agents (2016–Present). Molecules. 2020; 25(11):2666. https://doi.org/10.3390/molecules25112666
Chicago/Turabian StyleZhang, Qian, Pengwu Zheng, and Wufu Zhu. 2020. "Research Progress of Small Molecule VEGFR/c-Met Inhibitors as Anticancer Agents (2016–Present)" Molecules 25, no. 11: 2666. https://doi.org/10.3390/molecules25112666