Novel potent orally active multitargeted receptor tyrosine kinase inhibitors: synthesis, structure-activity relationships, and antitumor activities of 2-indolinone derivatives.
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Cho TP, Dong SY, Jun F, Hong FJ, Liang YJ, Lu X, Hua PJ, Li LY, Lei Z, Bing H, Ying Z, Qiong LF, Bei FB, Guang LL, Shen GA, Hong SG, Hong SW, Tai MX
Novel potent orally active multitargeted receptor tyrosine kinase inhibitors: synthesis, structure-activity relationships, and antitumor activities of 2-indolinone derivatives.
J Med Chem. 2010 Nov 25;53(22):8140-9. doi: 10.1021/jm101036c. Epub 2010 Oct 28.
- PubMed ID
- 21028894 [ View in PubMed]
- Abstract
The inhibition of receptor tyrosine kinases (RTKs) has become a successful approach in the development of anticancer agents. Many potent small-molecule kinase inhibitors have been discovered. We report herein a series of pyrrolo-fused-heterocycle-2-indolinone analogues as inhibitors of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and c-Kit. Among them, some pyrrolo-fused six- and seven-membered-heterocycle derivatives such as 9, 15, 23, and 25 are potent inhibitors of VEGFR, PDGFR, and c-Kit both enzymatically (<50 nM) and cellularly (<50 nM). Furthermore, compounds 9 and 25 possess favorable pharmacokinetic profiles and demonstrate good efficacies against human HT-29 cell colon tumor xenografts in nude mice. Further evaluations are in progress.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Sunitinib Platelet-derived growth factor receptor beta IC 50 (nM) 9 N/A N/A Details Sunitinib Vascular endothelial growth factor receptor 2 IC 50 (nM) 15 N/A N/A Details Sunitinib Vascular endothelial growth factor receptor 2 IC 50 (nM) 139 N/A N/A Details