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Eur J Med Chem. 2014 Jul 23;82:139-51. doi: 10.1016/j.ejmech.2014.05.051. Epub 2014 May 23.

Synthesis and in vivo SAR study of indolin-2-one-based multi-targeted inhibitors as potential anticancer agents.

Author information

1
Shandong Provincial Key Laboratory of Small Molecular Targeted drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
2
Shandong Provincial Key Laboratory of Small Molecular Targeted drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China. Electronic address: chuanwen.fan@qilu-pharma.com.

Abstract

A series of indolin-2-one analogues were designed and synthesized, and all of them exhibited excellent in vitro potency. The structure and in vivo activity or toxicity relationship (in-vivo SAR) investigation of indolin-2-one structural analogues was carried out. In vivo efficacy studies indicated that 3b significantly suppressed tumor growth in HT-29 and NCI-H460 xenografts without causing significant loss of body weight. Kinase assay showed that compound 3b effectively inhibited the VEGFR-2, VEGFR-3, FLT3, Ret and PDGFR-β kinases, but had little effect on the VEGFR-1 kinase. Besides, 3b showed higher selectivity for VEGFR-2 compared with PDGFR-β. On the basis of its selectivity and safety properties, 3b was identified as a drug candidate for the treatment of cancer.

KEYWORDS:

In-vivo SAR; Indolin-2-one analogues; Multi-targeted inhibitors; PDGFR-β; VEGFR-2

PMID:
24904961
DOI:
10.1016/j.ejmech.2014.05.051
[Indexed for MEDLINE]

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