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

Long Zhang; Qingmei Zheng; Yingying Yang; Haojie Zhou; Xingjiang Gong; Shuyong Zhao; Chuanwen Fan

doi:10.1016/j.ejmech.2014.05.051

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

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

Authors

Long Zhang¹, Qingmei Zheng¹, Yingying Yang¹, Haojie Zhou¹, Xingjiang Gong¹, Shuyong Zhao¹, Chuanwen Fan²

Affiliations

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.

PMID: 24904961
DOI: 10.1016/j.ejmech.2014.05.051

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HT29 Cells
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Mice
Molecular Structure
Neoplasms, Experimental / drug therapy*
Neoplasms, Experimental / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Kinases / metabolism*
Pyrroles / pharmacology
Structure-Activity Relationship
Sunitinib

Substances

Antineoplastic Agents
Indoles
Protein Kinase Inhibitors
Pyrroles
indolin-2-one
Protein Kinases
Sunitinib