Design,synthesis And New Pyrimidine Class FGFR Inhibitors In Vitro Anti-tumor Research

Fibroblast growth factors?FGFs?bind to their receptors(Fibroblast growth factor receptors?FGFRs?to activate their regulated downstream signaling pathways in fiber formation,embryogenesis,angiogenesis,metabolism,and many other proliferations.And plays an important role in biological processes such as the differentiation process.High expression,mutation,etc.of FGFR lead to abnormal activation of its signaling pathway,which is usually closely related to the occurrence and development of tumors.In recent years,a large number of studies have confirmed that blocking FGF-FGFR-mediated tumor signaling pathway can effectively inhibit tumor proliferation and metastasis.Therefore,FGFR has become a hot target for the development of anti-tumor drugs.Currently,some FGFR tyrosine kinase inhibitors?TKIs?have been undergoing Phase I/II clinical trials,but no inhibitors specifically targeting FGFRs have been marketed or used clinically.Since most of the kinase domains are highly similar,the first generation of FGFR TKIs?non-selective FGFR mainly including Dovitinib,Lucitanib,Lenvatinib,Ponatinib,and Nintedanib?generally inhibit various kinases other than FGFR?such as VEGFRs,PDGFRs,etc.?.These non-selective inhibitors usually cause large toxic side effects and are greatly limited in practical applications.Second-generation FGFR inhibitors such as AZD4547?JNJ-42756493?BGJ-398 and LY2874455 have higher FGFR selectivity than first-generation inhibitors and are expected to produce higher levels of clinical benefit and reduce the risk of adverse reactions.At present,it has been found that selective inhibitors of FGFR4?BLU554,H3B-6527 and FGF401?can effectively treat liver cancer,and can avoid some side effects caused by multi-target inhibitors.However,these drugs are still in the clinical research stage and have not been approved for clinical use by the FDA.In order to find a highly selective FGFR inhibitor with a novel mother core structure,a novel FGFR inhibitor of 5-substituted pyrimidines was designed and synthesized by using BGJ398 as a lead compound and transforming the mother nucleus or substituent.Screening for in vitro kinase activity and preliminary study of their anti-tumor structure-activity relationship.The results showed that the active compound 6i can effectively inhibit FGFR1 and FGFR4V550L with IC₅₀values of 62 nM and 37.925 nM,respectively.This compound provides a lead structure for the discovery of a high-efficiency inhibitor of FGFR.