Design, synthesis and biological evaluation of novel 1H-1,2,4-triazole, benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening

Jian Liu,Yu Wen,Lina Gao,Liang Gao,Fengjun He,Jingxian Zhou,Junwei Wang,Rupeng Dai,Xiaojing Chen,Di Kang,Lihong Hu

doi:10.1080/14756366.2019.1673745

Jian Liu, Yu Wen + Show 9 more

Open Access

https://doi.org/10.1080/14756366.2019.1673745

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Abstract

Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragment-based virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC50 = 15.0 nM) and modest anti-proliferative activity (IC50 = 785.8 nM). Through two rounds of optimisation, the indazole derivative 9 u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC50 = 3.3 nM) and cellular activity (IC50 = 468.2 nM). Moreover, 9 u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1.

Highlights

Protein kinases constitute one of the largest protein families in humans[1–5]
The kinase enzymes in this family catalyse phosphorylation of serine, threonine, or tyrosine residues, which regulate the majority of signal transduction pathways in cell, and play an important role in cell growth, metabolism, differentiation and apoptosis
Deregulation of protein kinases is implicated in a number of diseases including cancer, diabetes and inflammation

Summary

Introduction

Protein kinases constitute one of the largest protein families in humans[1–5]. The kinase enzymes in this family catalyse phosphorylation of serine, threonine, or tyrosine residues, which regulate the majority of signal transduction pathways in cell, and play an important role in cell growth, metabolism, differentiation and apoptosis . Deregulation of protein kinases is implicated in a number of diseases including cancer, diabetes and inflammation. Targeted inhibition of protein kinases has thereby become an attractive therapeutic strategy in treatment of relevant diseases[6,7]. Fibroblast growth-factor receptors (FGFRs) form a sub-family of the receptor tyrosine kinase (RTK) superfamily, which consists of four highly conserved functional members (FGFR 1–4)[8,9]. FGFR signalling is initiated by binding of extracellular FGF ligand which leads to receptor dimerisation and cross-phosphorylation

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