Design,Synthesis And Biological Evaluation Of Novel Selective Pan-FGFR Inhibitors

Fibroblast growth factor receptor（FGFR）is one of the important members of the receptor tyrosine kinase family.It is mainly composed of four subfamilies and plays a important role in human physiological regulation.However,abnormal activation of FGF/FGFR signaling pathway is caused by FGFR amplification,mutation and oncogenic fusion,which induces tumor cell proliferation and differentiation,promotes tumor development.Therefore,FGFR is considered to be an important target for the development of anti-tumor drugs.At present,most of FGFR inhibitors in clinic studied have only good inhibitory activities against FGFR（1-3）,but have a poor effect on FGFR4.Many researches have shown that abnormal FGF19/FGFR4 is closely related to the occurrence and development of liver cancer.Therefore,small molecule inhibitors targeting FGFR（1-4）will provide a wider range of therapeutic effects.Based on the previously discovered indazole FGFR（1-3）inhibitor 2-2 as a lead compound and form a covalent bond with Cys477 in the hinge region.A series of 2-wahead-N-（1H-indazole）benzamide derivatives（series 1-3）were designed by introducing acrylamide as a Michael addition acceptor on the near-solvent region benzene ring.In addition,a total of 38 new compounds（3-19a-n,3-24-a-x）were synthesized and biological evaluation.The synthesis and biological activity showed that the representative compounds 3-24b had IC₅₀ values of 5.9 and 15 nM for FGFR1 and FGFR4,respectively.It can effectively inhibit the proliferation of SNU-16 and Hep3B cells(IC₅₀=47.4 and 517.00 nM).In addition,the antitumor efficiency of FGFR inhibitors on tumor growth in SNU－16 xenograft model showed that when the dose of 10 mg/kg and once a day,3-24b was effective in inhibiting tumor growth with a tumor inhibition rate of 67.93%,and poor activity than positive control.In order to further improve the physicochemical properties and biological activity of compound 3-24b.We optimized the substituents in the near-solvent benzene ring（series 2-3）,and finally obtained excellent cell-active compounds 3-24i(SNU-16:IC₅₀= 7.0 nM and Hep3B:IC₅₀ = 143.70 nM),and the same level of cell activity was achieved for the positive compounds AZD4547 and BLU9931.At present,the metabolic stability,pharmacokinetics and in vivo pharmacodynamics of compounds 3-24i will be investigated.It is expected that the pan-FGFR inhibitors found in this research provide an important lead compound for the development of novel FGFR（1-4）inhibitors for the treatment of cancer patients.