Antitumor Pharmacodynamics Study Of Pan-FGFR Inhibitor Compound 9g

As the development of cancer research,biomedical technology innovation,analysis of human genome sequencing technology progress and the emergence big data analysis tools,Targeted tumor-driven genes and personalized molecular therapies for the indicated molecular types have become the mainstream of cancer therapy and have greatly accelerated the development of antitumor drugs.Receptor tyrosine kinase(RTKs)participates in a series of cell biological events that regulate cell proliferation,migration,differentiation and apoptosis.Its overexpression or overactivation closely relate to the development of tumor and become the key target of cancer treatment.Fibroblast growth factors receptors(FGFR1-4)are a subfamily of receptor tyrosine kinases(RTKs).Upon binding with fibroblast growth factors,FGFR induces dimerization and autophosphorylationon tyrosine residues,resulting in activation of downstream signaling including MEK-ERK,PI3K-Akt,and PLC?,which mediate several important physiological processes during embryogenesis,tissue repair,wound healing,and angiogenesis.Numerous evidences highlight that the activation of FGF/FGFR signaling plays a critical role in tumor progression and growth,Moreover,aberrant signaling of FGF/FGFR hasbeen frequently found in various cancers,including urothelial cancers,breast cancers,endometrial cancers,squamous lung cancers,ovarian cancers,and cholangiocarcinomas,etc.The abnormal mutation signals of FGFs/FGFRs mutation,amplification,overexpression,autocrine,paracrine and other mechanisms lead to the continuous activation of FGFR and promote the development of the tumor.At present,no selective inhibitors targeting FGFR have been listed.More than 30 inhibitors of FGFR in the world are in different stages of clinical research,mainly multitargeting tyrosine kinase inhibitors(TKIs),leading to serious adverse reactions,which will inhibit FGFR in clinical trials(in particular,the hypertension that occurs as a result of KDR inhibition).On the basis of these considerations,there has been an increasing interest in developing selective FGFR TKIs.An important branch of selective FGFR inhibitors is the irreversible inhibitor,which has a higher selectivity and better inhibitory activity than the reversible inhibitor.But at present,only a few of these selective inhibitors in the world,and they are all in the early stage of clinical practice.Therefor research of FGFR selective inhibitors with independent intellectual property rights is of great significance.As the development status of tumor therapy,this paper,carried out pharmacodynamic evaluation and characterization of FGFR inhibitors around tumor driven genes.The result show that,in molecular lever,Compound 9g significantly target inhibits FGFR1-4,with mean IC50 values of< 0.3,0.8,9.4,5.3 nM.however,it has almost no inhibitory effect on other tyrosine kinases,and achieves good selectivity;moreover,Compound 9g irreversibly binds to FGFR1;in cell lever,Compound 9g effectively inhibits the phosphorylation of FGFR and the downstream effectors PLC? and Erk in KG-1;In vitro Activity,Compound 9g significantly inhibited the proliferation of FGFR-driven cancer cell lines harboring genetic alterations in FGFR,with IC50 values of less than 1 nM against NCI-H1581,SNU-16,OPM-2 and RT-112,respectively.In vivo Antitumor Efficacy,9g dose-dependently suppressed the tumor progression in both xenograft models,with the maximum tumor growth inhibition rate(TGI)of 98.9% at the dose 100 mg/kg in NCI-H1581 model and 85.8% at the dose 50 mg/kg in SNU-16 model,respectively.The above result show that,we have described a irreversible pan-FGFR inhibitors,which have significant effect on anti-tumor activity,and provides a certain structural basis and material basis for the development of FGFR inhibitors.