Acenaphtho[1,2-b]pyrrole-based selective fibroblast growth factor receptors 1 (FGFR1) inhibitors: design, synthesis, and biological activity

Zhuo Chen; Xin Wang; Weiping Zhu; Xianwen Cao; Linjiang Tong; Honglin Li; Hua Xie; Yufang Xu; Shaoying Tan; Dong Kuang; Jian Ding; Xuhong Qian

doi:10.1021/jm200258t

Acenaphtho[1,2-b]pyrrole-based selective fibroblast growth factor receptors 1 (FGFR1) inhibitors: design, synthesis, and biological activity

J Med Chem. 2011 Jun 9;54(11):3732-45. doi: 10.1021/jm200258t. Epub 2011 May 13.

Authors

Zhuo Chen¹, Xin Wang, Weiping Zhu, Xianwen Cao, Linjiang Tong, Honglin Li, Hua Xie, Yufang Xu, Shaoying Tan, Dong Kuang, Jian Ding, Xuhong Qian

Affiliation

¹ School of Pharmacy, East China University of Science and Technology , Shanghai, China.

PMID: 21517068
DOI: 10.1021/jm200258t

Abstract

A novel series of acenaphtho[1,2-b]pyrrole derivatives as potent and selective inhibitors of fibroblast growth factor receptor 1 (FGFR1) were designed and synthesized. In silico target prediction revealed that tyrosine kinases might be the potential targets of the representative compound 2, which was subsequently validated by enzyme-linked immunosorbent assay (ELISA) for its selective and active FGFR1 inhibition of various tyrosine kinases. The structure-activity relationship (SAR) analysis aided by molecular docking simulation in the ATP-binding site demonstrated that acenaphtho[1,2-b]pyrrole carboxylic acid esters (2-5) are potent inhibitors of FGFR1 with IC(50) values ranging from 19 to 77 nM. Furthermore, these compounds exhibited favorable growth inhibition property against FGFR-expressing cancer cell lines with IC(50) values ranging from micromolar to submicromolar. Western blotting analysis showed that compounds 2, 3, and 2b inhibited activation of FGFR1 and extracellular-signal regulated kinase 1/2 (Erk1/2).

Publication types

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

MeSH terms

Acenaphthenes / chemical synthesis*
Acenaphthenes / chemistry
Acenaphthenes / pharmacology*
Acenaphthenes / toxicity
Animals
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
Extracellular Signal-Regulated MAP Kinases / metabolism
Goats
HeLa Cells
Humans
Inhibitory Concentration 50
Mice
Molecular Targeted Therapy
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / toxicity
Pyrroles / chemical synthesis*
Pyrroles / chemistry
Pyrroles / pharmacology*
Pyrroles / toxicity
Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
Receptor, Fibroblast Growth Factor, Type 1 / metabolism
Structure-Activity Relationship

Substances

Acenaphthenes
Protein Kinase Inhibitors
Pyrroles
ethyl 8-oxo-8H-acenaphtho(1,2-b)pyrrole-9-carboxylate
Receptor, Fibroblast Growth Factor, Type 1
Extracellular Signal-Regulated MAP Kinases