Design,Synthesis And Evaluate Of Novel Dual HDAC And FGFR1 Inhibitors Bearing An Indazole Scaffold

Nowadays,the design and development of dual inhibitors has become a research hotspot in the anti-tumor area.Researchers have obtained many multifunctional molecules which can inhibit two or more targets stimutaneously and avoid side effects and complex pharmacokinetics associated with the co-administration of drugs.It is worth noting that breakthroughs have been made in developing the dual inhibitors of histone deacetylase(HDAC)and protein tyrosine kinases,however,no report has attempted to design dual inhibitors of fibroblast growth factor receptor(FGFR)and HDAC.Both HDAC and FGFR are important trgets for cancer therapy,which is usually aberrantly activated and expressed in neoplastic tissue.Therefore,we aimed to designe and synthesize serials of dual HDAC/FGFR1 inhibitors,which can not only overcome the drug-resistance and side effects but also have high selectivity,low toxicity,and good efficacy.Starting from the compound C3,obtained from the FGFR inhibitor AZD4547 by scaffold hopping,and selective HDAC inhibitor Nexturastat A,molecular hybridization strategies were employed based on their binding mode with target protein,then the twenty-four derivatives of 1H-indazol-3-amine and benzohydroxamic acids scaffold were designed,synthesized and biologically evaluated.In the preliminary experiment,we obtained the hit compound A5.Although the compound showed better inhibitory activity against HDAC6 but the inhibitory activity against FGFR1 was poor,we have optimized the structure of the Region A.The 3-position ethoxyphenyl-substituted compound A7 was found with not only excellent activity at the molecular level but also high potency at the cellular level(HDAC6 IC50 = 32nM;FGFR1 IC50 = 473 nM;in vitro MCF-7 IC50 = 9.0?M;HL-60 IC50 = 0.9 ?M).Meanwhile,Compound A7 showed good selectivity against HDAC6,so,it was an excellent selective dual HDAC/FGFR1 target inhibitor.