Design, synthesis and biological evaluation of N-phenylthieno[2,3-d]pyrimidin-4-amines as inhibitors of FGFR1

A A Gryshchenko; V G Bdzhola; A O Balanda; N V Briukhovetska; I M Kotey; A G Golub; T P Ruban; L L Lukash; S M Yarmoluk

doi:10.1016/j.bmc.2014.12.044

Design, synthesis and biological evaluation of N-phenylthieno[2,3-d]pyrimidin-4-amines as inhibitors of FGFR1

Bioorg Med Chem. 2015 May 1;23(9):2287-93. doi: 10.1016/j.bmc.2014.12.044. Epub 2015 Mar 3.

Authors

A A Gryshchenko¹, V G Bdzhola², A O Balanda², N V Briukhovetska², I M Kotey², A G Golub³, T P Ruban², L L Lukash², S M Yarmoluk²

Affiliations

¹ Institute of Molecular Biology and Genetics NAS of Ukraine, 150 Akademika Zabolotnogo Str., Kyiv 03680, Ukraine. Electronic address: a.a.grischenko@imbg.org.ua.
² Institute of Molecular Biology and Genetics NAS of Ukraine, 150 Akademika Zabolotnogo Str., Kyiv 03680, Ukraine.
³ Otava Ltd, 65 400 Applewood Crescent, Unit 100, Vaughan, Ontario L4K 0C3, Canada.

PMID: 25817240
DOI: 10.1016/j.bmc.2014.12.044

Abstract

Fibroblast grow factor receptor 1 (FGFR1) is an important anti-cancer target that plays crucial role in oncogenesis and oncogenic angiogenesis. The structure-activity relationship (SAR) of N-phenylthieno[2,3-d]pyrimidin-4-amines was investigated. Binding of active compounds with FGFR1 kinase was analyzed by molecular modeling studies. Selected active thieno[2,3-d]pyrimidines were tested for selectivity and antiproliferative activity. The most active compounds, 3-({6-phenylthieno[2,3-d]pyrimidin-4-yl}amino)phenol and 3-({5-phenylthieno[2,3-d]pyrimidin-4-yl}amino)phenol have IC₅₀ 0.16 and 0.18 μM, respectively. The results presented here may help to identify new thienopyrimidines with optimized cell growth inhibitory activity which may be further used as anticancer agents.

Keywords: Drug design; FGFR1 inhibitor; Molecular modeling; Thienopyrimidines.

Publication types

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

MeSH terms

Cell Line, Tumor
Dose-Response Relationship, Drug
Drug Design*
Drug Evaluation, Preclinical
Humans
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis*
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
Receptor, Fibroblast Growth Factor, Type 1 / metabolism
Structure-Activity Relationship
Thiophenes / chemical synthesis*
Thiophenes / chemistry
Thiophenes / pharmacology*

Substances

Protein Kinase Inhibitors
Pyrimidines
Thiophenes
FGFR1 protein, human
Receptor, Fibroblast Growth Factor, Type 1